Stem Cells International

Stem Cells International / 2021 / Article

Review Article | Open Access

Volume 2021 |Article ID 6667735 | https://doi.org/10.1155/2021/6667735

Priscila Anhel Medrano-González, Osmar Rivera-Ramírez, Luis Felipe Montaño, Erika P. Rendón-Huerta, "Proteolytic Processing of CD44 and Its Implications in Cancer", Stem Cells International, vol. 2021, Article ID 6667735, 12 pages, 2021. https://doi.org/10.1155/2021/6667735

Proteolytic Processing of CD44 and Its Implications in Cancer

Academic Editor: Mustapha Najimi
Received15 Oct 2020
Revised04 Dec 2020
Accepted24 Dec 2020
Published06 Jan 2021

Abstract

CD44 is a transmembrane glycoprotein expressed in several healthy and tumor tissues. Modifications in its structure contribute differently to the activity of this molecule. One modification that has provoked interest is the consecutive cleavage of the CD44 extracellular ectodomain by enzymes that belong mainly to the family of metalloproteases. This process releases biologically active substrates, via alternative splice forms of CD44, that generate CD44v3 or v6 isoforms which participate in the transcriptional regulation of genes and proteins associated to signaling pathways involved in the development of cancer. These include the protooncogene tyrosine-protein kinase Src (c-Src)/signal transducer and activator of transcription 3 (STAT3), the epithelial growth factor receptor, the estrogen receptor, Wnt/βcatenin, or Hippo signaling pathways all of which are associated to cell proliferation, differentiation, or cancer progression. Whereas CD44 still remains as a very useful prognostic cell marker in different pathologies, the main topic is that the generation of CD44 intracellular fragments assists the regulation of transcriptional proteins involved in the cell cycle, cell metabolism, and most importantly, the regulation of some stem cell-associated markers.

1. Main Text

1.1. Structure and Function of CD44

CD44 is a cell surface adhesion molecule involved in cell-cell interactions, cell adhesion, and migration [1]. The main ligand of CD44 is hyaluronic acid (HA), a polysaccharide abundantly present in the extracellular matrix of mammals, yet it can bind to other components of the extracellular matrix and perform different functions depending on the structure of the protein it binds to [2, 3]. It is composed of a distal extracellular amino-terminal domain (ECD), a stem region, a transmembrane domain (TM), and an intracellular cytoplasmic carboxy-terminal domain (ICD) (Figure 1).

The CD44 gene encodes 20 exons, of which exons 6 to 15 correspond to variable exons (v1-v10). There is one standard isoform, designated CD44s and splice variants that contain variable exons, designated CD44v. The ECD structurally corresponds to a globular protein stabilized by disulfide bridges between three pairs of cysteine residues [2]. Carbohydrate chains, usually glycosaminoglycans (GAG) bind to this domain, which confer CD44 with a negative electric charge and rigidity [4]. The stem region is where the variable exons are inserted in the CD44v isoforms. The TM domain has an important role in the localization of CD44 on the cell surface [5], as a conserved cysteine residue in this region (cysteine 286) promotes its homodimerization and binding to HA [6, 7]. The ICD interacts with actin filaments through ezrin-radixin-moesin (ERM) proteins, which bind to CD44 through their amino-terminal FERM domain and to the actin cytoskeleton through their carboxyl-terminal domain [8]. The association between CD44 and the cytoskeleton allows the modulation of cell form and cellular motility [9]. The association between the ICD of CD44 and ERM proteins induces changes in the cytoskeleton architecture and allows the transduction of some signaling pathways since CD44 also interact as a coreceptor for a great amount of receptors [1013]. For example, the ICD participates in the activation of Ras through the recruitment of ERM proteins in the c-Met signaling pathway [10]. Nevertheless, associations of proteins such as a CD44-associated phosphatase 2A with the ICD, where ERM proteins do not have a clear role, have been reported in leukemic T cell apoptosis [14].

The crystallographic structure of the CD44 hyaluronic acid binding domain (CD44 HABD) has shown that it is composed of two alpha helices and two beta sheets constituted by six and three strands, respectively. After the binding of CD44 HABD to HA, a rearrangement in the beta strands, a β9 present in the HA-unbound state of CD44 HABD, is not present anymore, and a disorder of the molecule structure occurs [15].

CD44 alternative splicing generates a great amount of isoforms [16]. Ten of the exons contained in the gen are expressed in all the isoforms (constant exons), while the remaining ten central exons (variable exons) are added or eliminated in the stem region in different combinations in different isoforms (Figure 1). The standard isoform (CD44s) lacks all the variable exons and is expressed in most of the cells of vertebrate animals, while the variant isoforms (CD44v) are expressed only in some cells under specific conditions [17]. The ICD can be subject to alternative splicing too, since the differential use of exons 19 and 20 generates a short version with 3 amino-acid residues, and a longer version with 70 amino-acid residues, being the longer version the more abundant [1]. Additionally, different posttranslational modifications generate additional diversity in its structure. Interestingly, different isoforms of CD44 are known to acquire different functions depending on the variable exons included in its structure since they induce conformational changes that allow the new isoforms to generate new binding sites; for example, the sequence that is encoded by the variable exon 6 has a binding site for the hepatocyte growth factor (HGF) and for the vascular endothelial growth factor (VEGF) [18] while the variable exon 3 has an heparan sulfate-binding site that allows it to bind to some other growth factors such as the fibroblast growth factor (FGF) or the epidermal growth factor (EGF) [19].

In mammals, CD44 is expressed in hematopoietic lineage, endothelial cells, and epithelial cells [21]. The ECD has a highly conserved region (85% identity), which corresponds to exons 1-5, and a variable region where variable exons are inserted. The membrane-proximal region, encoded by exons 16 and 17, is less conserved (35%), while exon 18, which encodes the TM region, is 100% conserved [2]. The genomic structure of CD44 is highly conserved between humans and mice, and the length of the introns in the regions involved in alternative splicing is almost identical [22].

In humans, CD44 is expressed in numerous tissues, including the central nervous system, lungs, epidermis, liver, and pancreas, among others. The variable isoforms of CD44 have a more restricted distribution than CD44s, which suggests that the alternative splicing of this protein is a highly regulated process [23]. Additionally, the expression of distinctive isoforms of CD44 during different embryonic stages has been reported; for example, CD44v9 isoform is predominantly expressed in the epidermis, trachea, lungs, thyroid gland, mesonephric ducts, and paramesonephric ducts, while CD44v6 isoform can be detected in the epidermis and tracheas of 10th week human fetuses. In human fetal thymus, CD44s is expressed in the cortical region, while the CD44v9 isoform is expressed in medullary cells [24], thus establishing that the expression of different isoforms of CD44 can be tissue-specific and stage-specific. In T cells, CD44 interacts with CD4, forming a complex where, presumably, CD3 and the TCR are recruited to mediate the activation of T cells [25]. CD44 can be distributed in lipid rafts, where several molecules are recruited to facilitate signal transduction. The localization of CD44 in lipid rafts is positively regulated by the palmitoylation of cysteine residues, while the presence of phosphatidylinositol 4,5-bisphosphate (PIP2) decreases its affinity for lipid rafts [26]. Once located in lipid rafts, CD44 can suppress the binding of ERM proteins to the ICD, and in T cells, the binding of CD44 to HA can be regulated, participating in the regulation of adhesion and migration processes [27].

1.2. CD44 Expression and Cancer Stem Cells

In the late 1990s, a small subpopulation of cells in the hematopoietic and tissue cancers was identified [28]. This cell subpopulation shares characteristics with progenitor cells and stem cells, mainly its self-renewal property among other characteristic, so they have been called cancer stem cells (CSC). There is a strong belief that this subpopulation is responsible for the initiation, progression, metastasis, and tumor recurrence [29]. Among the different molecular markers that have been used to identify CSCs, CD44 stands out (Table 1) [30]. The expression of CD44 in cancer cells and in CSC of several types of tumor substantiates the highly important role of CD44 in the development and progression of cancer.


TumorCancer stem cell phenotype

BrainCD44+/CD133+/NPM1+/CD90+/CD49f+
BreastCD44+/CD24-/low/CD29+/ALDH1A3+h/CD164+
ColonCD44+/CD133+/CD26+/ALDH1+/EpCAM+h
Head and neckCD44+/CD271+
LeukemiaCD44+/CD123+/CD34+/CD38-
LiverCD44+/CD133+/CD24+/EpCAM+
LungCD44+/CD133+/ALDH1+/CDw338h
OvarianCD44+/CD24+/CD117+/CD133+/ALDH1+
MelanomaCD44+/CD15+/CD117+/CD34+/CD20+/ALDH1h
PancreasCD44+/CD133+/CD24+/EpCam+
ProstateCD44+/CD133+/21hintegrin

There are innumerable CSC phenotype combinations that depend on the histological type and the recurrence rate. Also, designated as breast cancer resistance protein or ATP-binding cassette transporter G2. Is the noncovalent heterodimer CD49b/CD29.
1.3. Interaction of CD44 with Surface Receptors

Hyaluronic acid, an anionic nonsulfated glycosaminoglycan, is the primary CD44 binding molecule (Wang L, Methods Mol Biol 2018). CD44 also interacts with other highly relevant receptors such as TM4SF5, a tetraspanin involved in G1/S progression phase [31], osteopontin [32, 33], or CD74, the receptor for the macrophage migration inhibitory factor that induces the cleavage and release of its cytosolic extracellular domain which regulates cell survival [34]; this interaction activates signaling pathways involved in survival and proliferation of the cancer cells [35]. In hepatocarcinoma cells, a physical interaction between CD44 and TM4SF5 through their extracellular domains was involved in the activation of the protooncogene tyrosine-protein kinase Src (c-Src)/signal transducer, and activator of transcription 3 (STAT3) signaling [36]. It is becoming clear that some CD44 isoforms such as CD44v3 or v6 are recruited in a ligand-dependent manner as coreceptors in the epithelial growth factor or estrogen receptor signaling pathways [37]. CD44 interacts with small hyaluronic acid oligosaccharides [38]; furthermore, CD44 can bind α5β1-integrin, lymphocytes mannose receptors, and a4b1-integrin a well-recognized receptor for the vascular cell adhesion molecule VCAM-1 [3941]. These interactions point to the importance of CD44 in the interaction and cellular communication with extracellular media components.

1.4. Enzymatic Cleavage of CD44

CD44 binds some metalloproteinases (MMPs), like MMP-2, MMP-9, MMP-14, MMP-15, MMP-16, MMP-24, and MMP-25, through their hemopexin domain in lamellipodia edges [42, 43] (Figure 2). CD44 interaction with MMP-9 on the cell surface of melanoma cells promotes the degradation of collagen IV and cell invasion [44]. Clustering of CD44 allows the retention of MMP-9, promoting its proteolytic activity on the membrane [45], but also and interestingly, the active form of MMP-2 coprecipitates with CD44, indicating its involvement in the enzyme activation [46].

CD44 forms a platform for the assembly of several MMPs with their substrates [47]. In normal mouse breast and uterine epithelium, the isoform CD44v3 recruits the active form of MMP-7 and the precursor of EGF, which bind to heparan sulfate-binding sites present in the exon v3; subsequently, ErbB4 is recruited, and survival signaling pathways are activated [48]. On the contrary, in some cancers such as in leukemia, MMP-2 and MMP-9 bind to CD44 in a complex where MMP-14, interacting with CD44v6, cleaves and activates MMP-2, inducing the degradation of the extracellular matrix [49]. The upregulation of CD147, also known as extracellular matrix metalloproteinase inducer, in epithelial cells leads to the formation of lipid raft-associated complexes composed of CD147, EGFR, and CD44, which activate the EGFR-Ras-ERK signaling pathway, facilitating chemoresistance processes, cell proliferation processes, and the activation of antiapoptotic signaling pathways [50]. However, other receptors with tyrosine kinase activity, like ErbB2 and ATP-binding cassette (ABC) transporters, may participate (Figure 2).

The interaction between these enzymes and CD44 generates the cleavage of its ECD, which is involved in the secretion and activation of MMP-9 [51]. The interaction between MMP-14 and CD44 promotes cell migration through a mechanism that is dependent on the cleavage of the ECD [52]. Interestingly, although CD44 binds to MMP-17 and MMP-25, CD44 is not cleaved [43]. In different models, ADAM10 and ADAM17 have been involved in the cleavage of CD44, mainly in melanoma cells [53, 54]. Most of the proteases that are involved in the cleavage of the ectodomain of CD44 are members of the MMPs or the ADAMs; however, the participation in this process of other enzymes such as cathepsin [55] or putative chymotrypsin-like serine proteinases [56], which are also able to cause the release of ECD, remains to be clarified.

1.5. Sequential Cleavage of CD44

CD44 can be found in three phases: a membrane receptor, an integral component of the extracellular matrix, and a soluble fragment present in fluids, where serine proteinases and MMPs are involved [57]. As mentioned before, cleavage of CD44 releases ECD fragments with a molecular weight in the 25 KDa range [58], suggesting the participation of several enzymes [35] as different cleavage sites can be exposed. In osteosarcoma cells, the spontaneous generation of 90 and 70 KDa ECD fragments has been observed, but when MMP-14 expression was induced, an additional 50 KDa fragment was also found. The latter strongly suggests that MMP-14 generated a fragment that was independent of posttranslational modifications [42]. The release of the ECD leaves 18-25 KDa truncated fragments in the cell membrane in articular chondrocytes of osteoarthritis patients and in prostate cancer cells [59, 60].

The cleavage of the ECD is a necessary step needed for the generation of the ICD by a mechanism called regulated intramembrane proteolysis (RIP) [16]. The latter is an evolutionarily conserved process characterized by the cleavage of transmembrane proteins and the release of cytosolic fragments [58, 61]. The CD44 ICD fragment is generated through the cleavage of the TM domain, by an enzyme complex formed by presenilin1-presenilin 2-γ-secretase [62, 63]. After the activity of this complex is exerted upon its substrate, fragments with different molecular weights are released. Nevertheless, there are some instances where a dual intramembrane cleavage mechanism generated by the secretase complex generates small CD44 peptides (a major 16 KDa fragment and 3 minor fragments of roughly 5 KDa, also called CD44 β) [59, 64], or as observed in breast cancer cell lines, small 17 KDa fragments can be generated from the ICD spontaneously [65]. The ICD fragments are able to translocate to the nucleus and promote the transcription of target genes through the 12-O-tetradecanoylphorbol-13-acetate-responsive element (TRE), or cooperate with CBP/p300 and enhance transcriptional activity [58] (Figure 2).

1.6. Mechanisms that Promote the Cleavage of CD44

The cleavage of the ectodomain is regulated by phorbol esters, suggesting an important role for protein kinase C (PKC) [66]. The treatment with phorbol esters or the use of an anti-CD44 antibody (mAb IM7) induced the cleavage of the ECD in mouse monocytes; this cleavage was accompanied by changes in the structure of actin filaments, in a process mediated by the activation of Rac1 and Cdc42 [67]. A mechanism has been described, where 12-O-tetradecanoylphorbol-13-acetate (TPA) and ionomycin (a calcium ionophore) induce an MMP-mediated cleavage through two different pathways: the first pathway is activated by the influx of Ca+2 and is independent of PKC activity, while the second pathway is activated by TPA and involves the participation of Rac [68]. The influx of Ca+2 regulates the interaction between calmodulin and ADAM10, inducing its activation; the stimulation with TPA leads to the activation of PKC and Rac, inducing the activation of ADAM17 [69].

The cleavage of CD44 ECD is also regulated by cytokines such as interleukin 1 [59], TGFβ1 [70] or interferon γ [71], and bacterial- and leukocyte-derived proteinases [57, 72], all of which induce the expression of MMP-14 and the release of the ECD [73].

Posttranslational modifications also regulate the cleavage of CD44. In melanocytes, a full or partial O-glycosylation of four serine-glycine motifs located in the membrane-proximal region is required for the spontaneous cleavage of the ECD; mutations in these sites impair this cleavage [74]. Interestingly, mutations in certain regions or posttranslational modifications in the ICD might impair the homodimerization of CD44 and impair the cleavage of the ECD, since they regulate the access of proteases to their recognition sites by inducing conformational changes [75, 76].

1.7. Cleavage Sites of the ECD

Three cleavage sites have been identified: Gly192-Tyr (CS1), Gly233-Ser (CS2), and Ser249-Gln (CS3). Cleavage at CS1 and CS3 happens during normal physiological processes. CS1 is recognized by MMP-14 in vitro, and it has been suggested that MMP-15, MMP-16, and MMP-24 may recognize CS1 and CS2; CS3 is thought to be recognized by a member of the ADAMs family of proteases [77]. There is evidence that MMP-14 also recognizes Arg186-Ser and Thr163-Asn sites [52], probably secondary to highly variable patterns of glycosylation in CD44; this variability could interfere with the recognition of the proper sites. ADAM10 recognizes the S230 residue. Trypsin recognizes the K196 residue, but other putative sites not exposed because of the three-dimensional structure of CD44 may exist [75].

1.8. Cleavage Sites of the ICD

Two cleavage sites have been identified: Ala278-Leu279 and Ile287-Ala288 [64]. The amino-acid residues 288-324 in CD44 composed the released fragment of ICD [58]. The use of a mutant CD44, whose residues 287-290 were deleted, abolished the cleavage of the ICD [58], indicating that this cleavage site is essential. The ICD fragment thus generated is responsible for transcriptional activation. The function of a small fragment, CD44-β, also released by ICD cleavage is unknown, but it has been proposed that it allows the efficient removal of the remaining fraction that is anchored to the cell membrane [64].

1.9. ICD as a Transcription Factor

After CD44 is cleaved by γ-secretase, the ICD fragment accumulates in the nucleus and performs different roles. The ICD regulates the expression of the transcription factor RUNX2, and it can interact with it as a nuclear cofactor [60]. Moreover, the ICD binds to the consensus sequence CCTGCG of CD44, called CD44-ICD response element (CIRE), in a site that is near to the binding site of RUNX2 in the promoter of MMP-9, where it regulates its expression; additionally, the CIRE sequence is present in some Hif1α-regulated genes thus regulating its expression under normoxic conditions, independently of Hif1α [78]. Under hypoxic conditions, the ICD can bind to HIF-2α, but not to HIF-1α, and induce its stabilization, which enhances the activation of HIF target genes [79].

The ICD is able to regulate the transcription of genes that have TPA response elements, including CD44, leading to a positive feedback [58]. Some ICD early responsive genes encode enzymes of the glycolysis pathway, such as ALDOC, PDK1, and PFKFB4 [78]. The ICD regulates the expression of PFKFB4 by interacting with the promoter of CREB [80]. Additionally, the ICD activates the transcription of interferon-induced genes such as gamma-interferon-inducible protein 16 (IFI16), interferon-induced transmembrane protein 3 (IFITM3), and INFβ, where the KR sequence of the ICD seems to be a nuclear translocation motif. Besides, the ICD binds to CREB, regulating the expression of genes, such as cyclin D1 [81]. The correlation in mRNA and protein levels between CD44 and PD-L1 demonstrated that the binding of the ICD to the regulatory sequence of PD-L1 promotes its expression [82]. Since no transactivation domains have been found yet, it is believed that the ICD requires the participation of neighboring transcription factors [83].

Interestingly, the ICD regulates and activates the expression of some transcription factors related to the maintenance of stem cell characteristics, such as SOX2 and Oct-4 [65]. The ICD is able to promote the expression of factors that are related to stemness via PFKFB4-mediated glucose metabolism under normoxic conditions [80].

1.10. ECD, ICD, and Inflammatory Processes

Cleavage of CD44 is involved in various pathologies. The soluble fragment of CD44 (sCD44), detected in serum of healthy humans, increases its concentration in inflammatory diseases such as systemic sclerosis, chronic periodontitis, aggressive periodontitis, endometriosis, pulmonary tuberculosis, sarcoidosis, open-angle glaucoma, and pouchitis [8491].

Additionally, there are some instances where the proteolytic cleavage of CD44 may contribute to the development of some nonmalignant diseases. The cleavage of CD44 by a membrane type-1 MMP, in type-1 diabetes, regulates the intraislet homing of diabetogenic cytotoxic T cells [92]. The concentration of sCD44, increased in synovial fluid of patients with rheumatoid arthritis, is related to partial suppression of T cell activation [93]; a similar T lymphocyte activation that correlates with low levels of sCD44 has been established in chronic pancreatitis [94].

1.11. Participation of CD44, Its Variants, and ICD in Cancer

CD44 can promote, inhibit, or have no effect on cell invasion, depending on its expression levels and the activity of enzymes that regulate its cleavage [95]. Actually, it regulates migration and invasion processes depending on variant isoforms created by alternative splicing [9]. Interestingly, this alternative splicing is regulated by mitogenic or oncogenic signals [96]. Despite originally being considered a receptor for hyaluronic acid, it has been observed that the interaction of CD44 with different-sized HA oligosaccharides, which could represent a sign of cellular distress especially in malignancies [97], triggers intracellular signaling pathways [98] that lead to an increase in the expression of MMP-14, cleavage of CD44, and cell migration [99]. The cleavage of CD44 facilitates the detachment from HA in the extracellular matrix, and the ICD fragment liberated by the cleavage process is capable to induce the expression of new CD44 molecules on the cell membrane, thus facilitating the binding to other sites [100]. Similarly, CD44 makes nonmetastatic cells more metastatic [101] probably related to the isoforms that the cell expresses as several CD44v isoforms are cancer stem cell markers [102] in pancreas, laryngeal, head, neck, stomach, colon, lung, breast, ovarian, prostate, glioma, leukemia, or lymphoma cancer [17].

A comparison of healthy versus malignant tissue showed CD44 overexpression in liver, colon, esophageal, kidney, thyroid, and rectal cancer, as well as in cholangiocarcinoma and pituitary adenoma [103108]. Nevertheless, this data should be complemented with the methylation state of the promoter of CD44 since there are instances where it is frequently hypermethylated [109, 110] and functions as a silencer of tumor progression [111]. Finally, we must not put aside the microenvironment where the tumor is developing, as there is evidence that under certain environment conditions, sCD44 competitively inhibits the binding of CD44 molecules to HA [112]. A study where ECD cleavage was induced in lung epithelium tumor cells pretreated either with oncostatin M alone or combined with TGFβ1 generated fragments with a higher affinity for HA than cells pretreated only with TGFβ1 [70].

Changes in the tissue expression patterns of different isoforms of CD44 can impair epithelial-mesenchymal interactions and contribute to the characteristic functional and structural disorganization found in cancer [2]. Migration of tumor cells and leukocytes involves cell adhesion mechanisms similar to those that happen during embryonic development and differentiation or those established during lymphocyte recirculation, organogenesis, and embryogenesis [24].

Downstream signal transduction is involved in cancer progression and signal transduction. Because CD44 lacks kinase activity, it can transduce signals via coupling its intracellular domain to adaptor proteins or kinases such as PI3K, NFkB, or CREB [113] and target downstream genes Survivin, Cortactin, and TGF-b2 all of which are related to cancer cell invasion [18, 114116]. TGF-β2 is known to regulate epithelial-mesenchymal transition in the breast [117]. In oral cancer, CD44v4 is associated to chemoresistance to cisplatin via the activation of the MEK/ERK1/2 pathway whereas CD44v6 is associated to invasiveness via the inactivation of the PI3K/AKT/GSK3B pathway [118] as it regulates MMP-9 expression [119]. CD44v6 positive gastric cells also survive longer and have lower apoptosis after cisplatin treatment [120]. CD44 promotes tumor resistance to ROS- and chemotherapy-induced stress by regulating some of the transcription coactivators of the tumor suppressor Hippo signaling pathway that consists of a cascade of conserved kinases and transcription coactivators [121, 122]. In chronic leukemia, CD44 promotes cell survival by regulating the expression of the antiapoptotic protein MCL1 via ERK and AKT activation [123]. CD44 also targets the canonical Wnt/β-catenin pathway and the EMT process [124, 125]. The increase in ICD diminishes Sox9 expression in articular chondrocytes thus diminishing the expression of genes associated to differentiation and favoring the expression of genes associated to stemness [126]. ICD also binds to CREB, and the dimer binds to PFKB4, a promoter that activates glycolysis and stemness in breast cancer cells [80], whereas in thyroid cancer cells, it facilitates the recruitment of cyclin D1 and thus cell proliferation [81]. Finally, in prostate cancer, ICD forms a complex with RUNX inducing the transcription of genes associated to migration and invasion such as MMP-9 and osteopontin [60](Figure 3).

2. Conclusions

The cleavage of CD44 happens in normal tissues as part of physiological processes. In tumor tissues, there are increased expressions of enzymes that mediate this cleavage as well as increased levels of sCD44. CD44 is deeply involved in metastasis processes as (1) it facilitates cell adhesion to blood vessels and transendothelial migration, (2) it contributes to the maintenance of stem characteristics in tumor cells through the stimulation of key signaling pathways, (3) it confers resistance to drugs through an increased expression of the MDR1 multidrug resistance gene, and (4) it confers resistance to apoptosis by modifying the expression levels of caspase 3 and 9. Tumors overexpressing CD44v isoforms such as CD44v6, CD44v9, and CD44v10 have a poor prognosis.

It is still uncertain whether the cleavage of the ECD or modifications in the ICD that induce the cleavage of the ECD can lead to different responses. This process could be a meticulously regulated mechanism that starts with the cleavage of the ECD (induced by the characteristics of the ICD) and ends in a specific transcriptional response. However, the spontaneous generation of the ECD via nonrecognized enzymes remains to be specified. Consequently, the possible distinctive mechanisms that regulate differential CD44 cleavage and participate in the transcriptional specificity of ECD and ICD fragments remain elusive.

The precise homeostatic mechanisms that are disrupted and lead to an exacerbated cleavage of CD44 (post transcriptional modifications, changes derived by an abnormal splicing, isoforms switching, and association to other unknown molecules) in pathological conditions remain to be comprehended. Understanding what triggers and regulates the process is imperative as this is a major mechanism used by cancer cells to proliferate, migrate, and transmute into an undifferentiated phenotype. Its expression is regulated epigenetically, or by miRNAs. CD44 modulates the activity of multiple cellular signaling components [127] and plays a key role in the regulation of epithelial to mesenchymal transition. Targeting well-recognized CD44 abnormal mechanism to block aberrantly activated signaling pathways in tumor cells by antibodies, peptides, aptamers, hyaluronic acid oligomers, or chemotherapy is a current priority, but to understand the precise regulatory role of CD44 intracellular domains in this complex activation of abnormal signaling pathways is beginning to be considered a priority.

Data Availability

This is a review article; therefore, there is no data availability.

Conflicts of Interest

The authors declare that no conflict of interest exists.

Acknowledgments

This work was supported by the Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (PAPIIT) grants IN218019 and IN221519, UNAM, México. This work is the result of the research project of Priscila Medrano, a student at the Biological Sciences Postgraduate Course, UNAM.

References

  1. D. Naor, R. V. Sionov, and D. Ish-Shalom, “CD44: Structure, Function and Association with the Malignant Process,” Advances in Cancer Research, vol. 71, pp. 241–319, 1997. View at: Publisher Site | Google Scholar
  2. S. Goodison, V. Urquidi, and D. Tarin, “CD44 cell adhesion molecules,” Journal of Clinical Pathology: Molecular Pathology, vol. 52, pp. 189–196, 1999. View at: Google Scholar
  3. P. Sil, N. Mateos, S. Nath et al., “Dynamic actin-mediated nano-scale clustering of CD44 regulates its meso-scale organization at the plasma membrane,” Molecular Biology of the Cell, vol. 31, no. 7, pp. 561–579, 2020. View at: Publisher Site | Google Scholar
  4. I. Gál, J. Lesley, W. Ko et al., “Role of the extracellular and cytoplasmic domains of CD44 in the rolling interaction of lymphoid cells with hyaluronan under physiologic flow,” The Journal of Biological Chemistry, vol. 278, no. 13, pp. 11150–11158, 2003. View at: Publisher Site | Google Scholar
  5. K. Buscher, S. B. Riese, M. Shakibaei et al., “The transmembrane domains of L-selectin and CD44 regulate receptor cell surface positioning and leukocyte adhesion under flow,” The Journal of Biological Chemistry, vol. 285, no. 18, pp. 13490–13497, 2010. View at: Publisher Site | Google Scholar
  6. D. Liu and M. S. Sy, “A cysteine residue located in the transmembrane domain of CD44 is important in binding of CD44 to hyaluronic acid,” The Journal of Experimental Medicine, vol. 183, no. 5, pp. 1987–1994, 1996. View at: Publisher Site | Google Scholar
  7. D. Liu and M. S. Sy, “Phorbol myristate acetate stimulates the dimerization of CD44 involving a cysteine in the transmembrane domain,” Journal of Immunology, vol. 159, pp. 2702–2711, 1997. View at: Google Scholar
  8. S. Tsukita, K. Oishi, N. Sato, J. Sagara, A. Kawai, and S. Tsukita, “ERM family members as molecular linkers between the cell surface glycoprotein CD44 and actin-based cytoskeletons,” The Journal of Cell Biology, vol. 126, no. 2, pp. 391–401, 1994. View at: Publisher Site | Google Scholar
  9. L. T. Senbanjo and M. A. Chellaiah, “CD44: a multifunctional cell surface adhesion receptor is a regulator of progression and metastasis of cancer cells,” Frontiers in Cell and Development Biology, vol. 5, 2017. View at: Publisher Site | Google Scholar
  10. V. Orian-Rousseau, H. Morrison, A. Matzke et al., “Hepatocyte growth factor-induced Ras activation requires ERM proteins linked to both CD44v6 and F-actin,” Molecular Biology of the Cell, vol. 18, no. 1, pp. 76–83, 2007. View at: Publisher Site | Google Scholar
  11. L. Y. W. Bourguignon, P. A. Singleton, H. Zhu, and B. Zhou, “Hyaluronan promotes signaling interaction between CD44 and the transforming growth factor β receptor I in metastatic breast tumor cells,” The Journal of Biological Chemistry, vol. 277, no. 42, pp. 39703–39712, 2002. View at: Publisher Site | Google Scholar
  12. K. Wakahara, H. Kobayashi, T. Yagyu et al., “Bikunin down-regulates heterodimerization between CD44 and growth factor receptors and subsequently suppresses agonist-mediated signaling,” Journal of Cellular Biochemistry, vol. 94, no. 5, pp. 995–1009, 2005. View at: Publisher Site | Google Scholar
  13. R. S. Peterson, R. A. Andhare, K. T. Rousche et al., “CD44 modulates Smad1 activation in the BMP-7 signaling pathway,” The Journal of Cell Biology, vol. 166, no. 7, pp. 1081–1091, 2004. View at: Publisher Site | Google Scholar
  14. M. Rajasagi, A. von Au, R. Singh, N. Hartmann, M. Zöller, and R. Marhaba, “Anti-CD44 induces apoptosis in T lymphoma via mitochondrial depolarization,” Journal of Cellular and Molecular Medicine, vol. 14, no. 6B, pp. 1453–1467, 2010. View at: Publisher Site | Google Scholar
  15. M. Takeda, S. Ogino, R. Umemoto et al., “Ligand-induced structural changes of the CD44 hyaluronan-binding domain revealed by NMR,” The Journal of Biological Chemistry, vol. 281, no. 52, pp. 40089–40095, 2006. View at: Publisher Site | Google Scholar
  16. R. F. Thorne, J. W. Legg, and C. M. Isacke, “The role of the CD44 transmembrane and cytoplasmic domains in co-ordinating adhesive and signalling events,” Journal of Cell Science, vol. 117, Part 3, pp. 373–380, 2004. View at: Publisher Site | Google Scholar
  17. Y. Yan, X. Zuo, and D. Wei, “Concise review: emerging role of CD44 in cancer stem cells: a promising biomarker and therapeutic target,” Stem Cells Translational Medicine, vol. 4, no. 9, pp. 1033–1043, 2015. View at: Publisher Site | Google Scholar
  18. M. Tremmel, A. Matzke, I. Albrecht et al., “A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis,” Blood, vol. 114, no. 25, pp. 5236–5244, 2009. View at: Publisher Site | Google Scholar
  19. K. L. Bennett, D. G. Jackson, J. C. Simon et al., “Cd44 isoforms containing exon V3 are responsible for the presentation of heparin-binding growth factor,” The Journal of Cell Biology, vol. 128, no. 4, pp. 687–698, 1995. View at: Publisher Site | Google Scholar
  20. S. Misra, V. C. Hascall, R. R. Markwald, and S. Ghatak, “Interactions between hyaluronan and its receptors (CD44, RHAMM) regulate the activities of inflammation and cancer,” Frontiers in Immunology, vol. 6, 2015. View at: Publisher Site | Google Scholar
  21. T. Tanaka, “Leukocyte Adhesion Molecules,” Encyclopedia of Immunobiology, vol. 3, pp. 505–511, 2016. View at: Google Scholar
  22. M. V. Bell, A. E. Cowper, M.-P. Lefranc, J. I. Bell, and G. R. Screaton, “Influence of intron length on alternative splicing of CD44,” Molecular and Cellular Biology, vol. 18, no. 10, pp. 5930–5941, 1998. View at: Publisher Site | Google Scholar
  23. R. J. S. Sneath and D. C. Mangham, “The normal structure and function of CD44 and its role in neoplasia,” Journal of Clinical Pathology-Molecular Pathology, vol. 51, pp. 191–200, 1998. View at: Google Scholar
  24. P. Ruiz, C. Schwärzler, and U. Günthert, “CD44 isoforms during differentiation and development,” BioEssays, vol. 17, no. 1, pp. 17–24, 1995. View at: Publisher Site | Google Scholar
  25. U. Dianzani, M. Bragardo, A. Tosti et al., “CD44 signaling through p56lck involves lateral association with CD4 in human CD4+ T cells,” International Immunology, vol. 11, no. 7, pp. 1085–1092, 1999. View at: Publisher Site | Google Scholar
  26. F. Sun, C. F. E. Schroer, C. R. Palacios, L. Xu, S. Z. Luo, and S. J. Marrink, “Molecular mechanism for bidirectional regulation of CD44 for lipid raft affiliation by palmitoylations and PIP2,” PLoS Computational Biology, vol. 16, no. 4, article e1007777, 2020. View at: Publisher Site | Google Scholar
  27. T. Murai, “Lipid raft-mediated regulation of hyaluronan-CD44 interactions in inflammation and cancer,” Frontiers in Immunology, vol. 6, 2015. View at: Publisher Site | Google Scholar
  28. T. Reya, S. J. Morrison, M. F. Clarke, and I. L. Weissman, “Stem cells, cancer, and cancer stem cells,” Nature, vol. 414, no. 6859, pp. 105–111, 2001. View at: Publisher Site | Google Scholar
  29. A. Z. Ayob and T. S. Ramasamy, “Cancer stem cells as key drivers of tumour progression,” Journal of Biomedical Science, vol. 25, no. 1, p. 20, 2018. View at: Publisher Site | Google Scholar
  30. W. Mitku, W. Tesfaye, and A. Wubshet, “Review on stem cell therapy and their role incCancer treatment,” International Journal of Biotechnology and Bioengineering, vol. 3, pp. 71–79, 2017. View at: Google Scholar
  31. J. W. Jung, S. J. Y. Macalino, M. Cui et al., “Transmembrane 4 L six family member 5 senses arginine for mTORC1 signaling,” Cell Metabolism, vol. 29, p. 1319, 2019. View at: Google Scholar
  32. I. Morath, T. N. Hartmann, and V. Orian-Rousseau, “CD44: more than a mere stem cell marker,” The International Journal of Biochemistry & Cell Biology, vol. 81, Part A, pp. 166–173, 2016. View at: Publisher Site | Google Scholar
  33. J. D. Klement, A. V. Paschall, P. S. Redd et al., “An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion,” The Journal of Clinical Investigation, vol. 128, no. 12, pp. 5549–5560, 2018. View at: Publisher Site | Google Scholar
  34. N. Gil-Yarom, L. Radomir, L. Sever et al., “CD74 is a novel transcription regulator,” Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 3, pp. 562–567, 2017. View at: Publisher Site | Google Scholar
  35. H. Al Ssadh, P. S. Spencer, W. Alabdulmenaim et al., “Measurements of heterotypic associations between cluster of differentiation CD74 and CD44 in human breast cancer-derived cells,” Oncotarget, vol. 8, no. 54, pp. 92143–92156, 2017. View at: Publisher Site | Google Scholar
  36. D. Lee, J. Na, J. Ryu et al., “Interaction of tetraspan(in) TM4SF5 with CD44 promotes self-renewal and circulating capacities of hepatocarcinoma cells,” Hepatology, vol. 61, no. 6, pp. 1978–1997, 2015. View at: Publisher Site | Google Scholar
  37. I. Morath, C. Jung, R. Lévêque et al., “Differential recruitment of CD44 isoforms by ERBB ligands reveals an involvement of CD44 in breast cancer,” Oncogene, vol. 37, no. 11, pp. 1472–1484, 2018. View at: Publisher Site | Google Scholar
  38. H. Kobayashi, M. Suzuki, N. Kanayama, T. Nishida, M. Takigawa, and T. Terao, “CD44 stimulation by fragmented hyaluronic acid induces upregulation of urokinase-type plasminogen activator and its receptor and subsequently facilitates invasion of human chondrosarcoma cells,” International Journal of Cancer, vol. 102, no. 4, pp. 379–389, 2002. View at: Publisher Site | Google Scholar
  39. S. McFarlane, C. McFarlane, N. Montgomery, A. Hill, and D. J. J. Waugh, “CD44-mediated activation of α5β1-integrin, cortactin and paxillin signaling underpins adhesion of basal-like breast cancer cells to endothelium and Fibronectin-enriched matrices,” Oncotarget, vol. 6, no. 34, pp. 36762–36773, 2015. View at: Publisher Site | Google Scholar
  40. M. Salmi, M. Karikoski, K. Elima, P. Rantakari, and S. Jalkanen, “CD44 binds to macrophage mannose receptor on lymphatic endothelium and supports lymphocyte migration via afferent lymphatics,” Circulation Research, vol. 112, no. 12, pp. 1577–1582, 2013. View at: Publisher Site | Google Scholar
  41. S. P. Thankamony and R. Sackstein, “Enforced hematopoietic cell E- and L-selectin ligand (HCELL) expression primes transendothelial migration of human mesenchymal stem cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 6, pp. 2258–2263, 2011. View at: Publisher Site | Google Scholar
  42. H. Mori, T. Tomari, N. Koshikawa et al., “CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain,” The EMBO Journal, vol. 21, no. 15, pp. 3949–3959, 2002. View at: Publisher Site | Google Scholar
  43. N. Suenaga, H. Mori, Y. Itoh, and M. Seiki, “CD44 binding through the hemopexin-like domain is critical for its shedding by membrane-type 1 matrix metalloproteinase,” Oncogene, vol. 24, no. 5, pp. 859–868, 2005. View at: Publisher Site | Google Scholar
  44. Q. Yu and I. Stamenkovic, “Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion,” Genes & Development, vol. 13, pp. 35–48, 1999. View at: Google Scholar
  45. S. T. Peng, C. H. Su, C. C. Kuo, C. F. Shaw, and H. S. Wang, “CD44 crosslinking-mediated matrix metalloproteinase-9 relocation in breast tumor cells leads to enhanced metastasis,” International Journal of Oncology, vol. 31, no. 5, pp. 1119–1126, 2007. View at: Google Scholar
  46. V. Samanna, H. Wei, D. Ego-Osuala, and M. A. Chellaiah, “Alpha-V-dependent outside-in signaling is required for the regulation of CD44 surface expression, MMP-2 secretion, and cell migration by osteopontin in human melanoma cells,” Experimental Cell Research, vol. 312, no. 12, pp. 2214–2230, 2006. View at: Publisher Site | Google Scholar
  47. B. Cauwe, P. E. V. Steen, and G. Opdenakker, “The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases,” Critical Reviews in Biochemistry and Molecular Biology, vol. 42, pp. 113–185, 2008. View at: Google Scholar
  48. W. H. Yu, Woessner JF Jr, J. D. McNeish, and I. Stamenkovic, “CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling,” Genes & Development, vol. 16, no. 3, pp. 307–323, 2002. View at: Publisher Site | Google Scholar
  49. M. Zöller, “CD44, hyaluronan, the hematopoietic stem cell, and leukemia-initiating cells,” Frontiers in Immunology, vol. 6, p. 235, 2015. View at: Google Scholar
  50. G. D. Grass, L. Dai, Z. Qin, C. Parsons, and B. P. Toole, Advances in Cancer Research, vol. 123, Academic Press Inc., 2014.
  51. C. Chetty, S. K. Vanamala, C. S. Gondi, D. H. Dinh, M. Gujrati, and J. S. Rao, “MMP-9 induces CD44 cleavage and CD44 mediated cell migration in glioblastoma xenograft cells,” Cellular Signalling, vol. 24, no. 2, pp. 549–559, 2012. View at: Publisher Site | Google Scholar
  52. M. Kajita, Y. Itoh, T. Chiba et al., “Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration,” The Journal of Cell Biology, vol. 153, no. 5, pp. 893–904, 2001. View at: Publisher Site | Google Scholar
  53. U. Anderegg, T. Eichenberg, T. Parthaune et al., “ADAM10 is the constitutive functional sheddase of CD44 in human melanoma cells,” The Journal of Investigative Dermatology, vol. 129, no. 6, pp. 1471–1482, 2009. View at: Publisher Site | Google Scholar
  54. M. Kawaguchi and V. J. Hearing, “The roles of ADAMs family proteinases in skin diseases,” Enzyme Research, vol. 2011, 9 pages, 2011. View at: Publisher Site | Google Scholar
  55. B. Sobotič, M. Vizovišek, R. Vidmar et al., “Proteomic identification of cysteine cathepsin substrates shed from the surface of cancer cells,” Molecular & Cellular Proteomics, vol. 14, no. 8, pp. 2213–2228, 2015. View at: Publisher Site | Google Scholar
  56. M. C. Lee, M. L. Alpaugh, M. Nguyen, M. Deato, L. Dishakjian, and S. H. Barsky, “Myoepithelial-specific CD44 shedding is mediated by a putative chymotrypsin-like sheddase,” Biochemical and Biophysical Research Communications, vol. 279, no. 1, pp. 116–123, 2000. View at: Publisher Site | Google Scholar
  57. J. Cichy and E. Puré, “The liberation of CD44,” Journal of Cell Biology, vol. 161, no. 5, pp. 839–843, 2003. View at: Publisher Site | Google Scholar
  58. I. Okamoto, Y. Kawano, D. Murakami et al., “Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway,” The Journal of Cell Biology, vol. 155, no. 5, pp. 755–762, 2001. View at: Publisher Site | Google Scholar
  59. N. Takahashi, C. B. Knudson, S. Thankamony et al., “Induction of CD44 cleavage in articular chondrocytes,” Arthritis and Rheumatism, vol. 62, no. 5, pp. 1338–1348, 2010. View at: Publisher Site | Google Scholar
  60. L. T. Senbanjo, H. Aljohani, S. Majumdar, and M. A. Chellaiah, “Characterization of CD44 intracellular domain interaction with RUNX2 in PC3 human prostate cancer cells,” Cell Communication and Signaling: CCS, vol. 17, no. 1, p. 80, 2019. View at: Publisher Site | Google Scholar
  61. M. S. Brown, J. Ye, R. B. Rawson, and J. L. Goldstein, “Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans,” Cell, vol. 100, no. 4, pp. 391–398, 2000. View at: Publisher Site | Google Scholar
  62. M. Medina and C. G. Dotti, “RIPped out by presenilin-dependent γ-secretase,” Cellular Signalling, vol. 15, no. 9, pp. 829–841, 2003. View at: Publisher Site | Google Scholar
  63. D. Murakami, I. Okamoto, O. Nagano et al., “Presenilin-dependent _γ_ -secretase activity mediates the intramembranous cleavage of CD44,” Oncogene, vol. 22, no. 10, pp. 1511–1516, 2003. View at: Publisher Site | Google Scholar
  64. S. Lammich, M. Okochi, M. Takeda et al., “Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Aβ-like peptide,” The Journal of Biological Chemistry, vol. 277, no. 47, pp. 44754–44759, 2002. View at: Publisher Site | Google Scholar
  65. Y. Cho, H. W. Lee, H. G. Kang, H. Y. Kim, S. J. Kim, and K. H. Chun, “Cleaved CD44 intracellular domain supports activation of stemness factors and promotes tumorigenesis of breast cancer,” Oncotarget, vol. 6, no. 11, pp. 8709–8721, 2015. View at: Publisher Site | Google Scholar
  66. K. Hayashida, A. H. Bartlett, Y. Chen, and P. W. Park, “Molecular and cellular mechanisms of ectodomain shedding,” The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology, vol. 293, no. 6, pp. 925–937, 2010. View at: Publisher Site | Google Scholar
  67. M. Shi, K. Dennis, J. J. Peschon, R. Chandrasekaran, and K. Mikecz, “Antibody-induced shedding of CD44 from adherent cells is linked to the assembly of the cytoskeleton,” Journal of Immunology, vol. 167, no. 1, pp. 123–131, 2001. View at: Publisher Site | Google Scholar
  68. I. Okamoto, Y. Kawano, M. Matsumoto et al., “Regulated CD44 cleavage under the control of protein kinase C, calcium influx, and the rho family of small G proteins,” The Journal of Biological Chemistry, vol. 274, no. 36, pp. 25525–25534, 1999. View at: Publisher Site | Google Scholar
  69. O. Nagano, D. Murakami, D. Hartmann et al., “Cell-matrix interaction via CD44 is independently regulated by different metalloproteinases activated in response to extracellular Ca2+ influx and PKC activation,” The Journal of Cell Biology, vol. 165, no. 6, pp. 893–902, 2004. View at: Publisher Site | Google Scholar
  70. J. Cichy, P. Kulig, and E. Puré, “Regulation of the release and function of tumor cell-derived soluble CD44,” Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, vol. 1745, no. 1, pp. 59–64, 2005. View at: Publisher Site | Google Scholar
  71. A. C. Newby, “Metalloproteinase production from macrophages – a perfect storm leading to atherosclerotic plaque rupture and myocardial infarction,” Experimental Physiology, vol. 101, no. 11, pp. 1327–1337, 2016. View at: Publisher Site | Google Scholar
  72. J. Cichy, R. Bals, J. Potempa, A. Mani, and E. Puré, “Proteinase-mediated release of epithelial cell-associated CD44 extracellular CD44 complexes with components of cellular matrices,” The Journal of Biological Chemistry, vol. 277, pp. 44440–44447, 2002. View at: Google Scholar
  73. Y.-C. Kuo, C. H. Su, C. Y. Liu, T. H. Chen, C. P. Chen, and H. S. Wang, “Transforming growth factor-β induces CD44 cleavage that promotes migration of MDA-MB-435s cells through the up-regulation of membrane type 1-matrix metalloproteinase,” International Journal of Cancer, vol. 124, no. 11, pp. 2568–2576, 2009. View at: Publisher Site | Google Scholar
  74. A. Gasbarri, F. del Prete, L. Girnita, M. P. Martegani, P. G. Natali, and A. Bartolazzi, “CD44s adhesive function spontaneous and PMA-inducible CD44 cleavage are regulated at post-translational level in cells of melanocytic lineage,” Melanoma Research, vol. 13, no. 4, pp. 325–337, 2003. View at: Publisher Site | Google Scholar
  75. L. M. Parra, M. Hartmann, S. Schubach, J. Ma, P. Herrlich, and A. Herrlich, “Growth factor and co-receptor release by structural regulation of substrate metalloprotease accessibility,” Scientific Reports, vol. 6, pp. 1–10, 2016. View at: Google Scholar
  76. M. Hartmann, L. M. Parra, A. Ruschel et al., “Inside-out regulation of ectodomain cleavage of cluster-of-differentiation-44 (CD44) and of neuregulin-1 requires substrate dimerization,” The Journal of Biological Chemistry, vol. 290, no. 28, pp. 17041–17054, 2015. View at: Publisher Site | Google Scholar
  77. H. Nakamura, N. Suenaga, K. Taniwaki et al., “Constitutive and induced CD44 shedding by ADAM-like proteases and membrane-type 1 matrix metalloproteinase,” Cancer Research, vol. 64, no. 3, pp. 876–882, 2004. View at: Publisher Site | Google Scholar
  78. K. E. Miletti-González, K. Murphy, M. N. Kumaran et al., “Identification of function for CD44 intracytoplasmic domain (CD44-ICD): modulation of matrix metalloproteinase 9 (MMP-9) transcription via novel promoter response element,” The Journal of Biological Chemistry, vol. 287, no. 23, pp. 18995–19007, 2012. View at: Publisher Site | Google Scholar
  79. E. Johansson, E. S. Grassi, V. Pantazopoulou et al., “CD44 interacts with HIF-2α to modulate the hypoxic phenotype of perinecrotic and perivascular glioma cells,” Cell Reports, vol. 20, no. 7, pp. 1641–1653, 2017. View at: Publisher Site | Google Scholar
  80. R. Gao, D. Li, J. Xun et al., “CD44ICD promotes breast cancer stemness via PFKFB4-mediated glucose metabolism,” Theranostics, vol. 8, no. 22, pp. 6248–6262, 2018. View at: Publisher Site | Google Scholar
  81. V. de Falco, A. Tamburrino, S. Ventre et al., “CD44 proteolysis increases CREB phosphorylation and sustains proliferation of thyroid cancer cells,” Cancer Research, vol. 72, no. 6, pp. 1449–1458, 2012. View at: Publisher Site | Google Scholar
  82. T. Kong, R. Ahn, K. Yang et al., “CD44 promotes PD-L1 expression and its tumor-intrinsic function in breast and lung cancers,” Cancer Research, vol. 80, no. 3, pp. 444–457, 2020. View at: Publisher Site | Google Scholar
  83. K. Schultz, C. Grieger (Lindner), Y. Li et al., “Gamma secretase dependent release of the CD44 cytoplasmic tail upregulates IFI16 in cd44 -/- tumor cells, MEFs and macrophages,” PLoS One, vol. 13, no. 12, article e0207358, 2018. View at: Publisher Site | Google Scholar
  84. S. Katoh, J. B. McCarthy, and P. W. Kincade, “Characterization of soluble CD44 in the circulation of mice. Levels are affected by immune activity and tumor growth,” Journal of Immunology, vol. 153, no. 8, pp. 3440–3449, 1994. View at: Google Scholar
  85. K. Komura, S. Sato, M. Fujimoto, M. Hasegawa, and K. Takehara, “Elevated levels of circulating CD44 in patients with systemic sclerosis: association with a milder subset,” Rheumatology, vol. 41, no. 10, pp. 1149–1154, 2002. View at: Publisher Site | Google Scholar
  86. S. Kaur, S. Narayanswamy, and A. V. Ramesh, “Comparative evaluation of salivary soluble CD44 levels in periodontal health and disease,” Journal of Indian Society of Periodontology, vol. 18, no. 6, pp. 734–738, 2014. View at: Publisher Site | Google Scholar
  87. A. Pazhohan, F. Amidi, F. Akbari-Asbagh et al., “Expression and shedding of CD44 in the endometrium of women with endometriosis and modulating effects of vitamin D: a randomized exploratory trial,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 178, pp. 150–158, 2018. View at: Publisher Site | Google Scholar
  88. B. Shiratori, J. Zhao, M. Okumura et al., “Immunological roles of elevated plasma levels of matricellular proteins in Japanese patients with pulmonary tuberculosis,” International Journal of Molecular Sciences, vol. 18, p. 19, 2017. View at: Google Scholar
  89. I. Kasuga, K. Minemura, H. Nasu et al., “Elevated serum soluble CD44 level in sarcoidosis,” International Journal of Molecular Medicine, vol. 6, no. 6, pp. 679–682, 2000. View at: Publisher Site | Google Scholar
  90. P. A. Knepper, A. M. Miller, J. Choi et al., “Hypophosphorylation of aqueous humor sCD44 and primary open-angle glaucoma,” Investigative Ophthalmology and Visual Science, vol. 46, no. 8, pp. 2829–2837, 2005. View at: Publisher Site | Google Scholar
  91. A. Stallmach, M. van Look, F. Scheiffele et al., “IgG, albumin, and sCD44 in whole-gut lavage fluid are useful clinical markers for assessing the presence and activity of pouchitis,” International Journal of Colorectal Disease, vol. 14, no. 1, pp. 35–40, 1999. View at: Publisher Site | Google Scholar
  92. A. Savinov and A. Strongin, “Defining the roles of T cell membrane proteinase and CD44 in type 1 diabetes,” IUBMB Life, vol. 59, no. 1, pp. 6–13, 2007. View at: Publisher Site | Google Scholar
  93. B. F. Haynes, L. P. Hale, K. L. Patton, M. E. Martin, and R. M. McCallum, “Measurement of an adhesion molecule as an indicator of inflammatory disease activity: up-regulation of the receptor for hyaluronate (CD44) in rheumatoid arthritis,” Arthritis and Rheumatism, vol. 34, no. 11, pp. 1434–1443, 1991. View at: Publisher Site | Google Scholar
  94. W. Schlosser, F. Gansauge, S. Schlosser, S. Gansauge, and H. G. Beger, “Low serum levels of CD44, CD44v6, and neopterin indicate immune dysfunction in chronic pancreatitis,” Pancreas, vol. 23, no. 4, pp. 335–340, 2001. View at: Publisher Site | Google Scholar
  95. R. Marrero-Diaz, J. J. Bravo-Cordero, D. Megías et al., “Polarized MT1-MMP-CD44 interaction and CD44 cleavage during cell retraction reveal an essential role for MT1-MMP in CD44-mediated invasion,” Cell Motility and the Cytoskeleton, vol. 66, no. 1, pp. 48–61, 2009. View at: Publisher Site | Google Scholar
  96. L. Prochazka, R. Tesarik, and J. Turanek, “Regulation of alternative splicing of CD44 in cancer,” Cellular Signalling, vol. 26, no. 10, pp. 2234–2239, 2014. View at: Publisher Site | Google Scholar
  97. R. Stern, “Hyaluronidases in cancer biology,” Seminars in Cancer Biology, vol. 18, no. 4, pp. 275–280, 2008. View at: Publisher Site | Google Scholar
  98. B. V. Nusgens, “Hyaluronic acid and extracellular matrix: a primitive molecule?” Annales de Dermatologie et de Vénéréologie, vol. 137, pp. S3–S8, 2010. View at: Publisher Site | Google Scholar
  99. C. I. KUNG, C. Y. CHEN, C. C. YANG, C. Y. LIN, T. H. CHEN, and H. S. WANG, “Enhanced membrane-type 1 matrix metalloproteinase expression by hyaluronan oligosaccharides in breast cancer cells facilitates CD44 cleavage and tumor cell migration,” Oncology Reports, vol. 28, no. 5, pp. 1808–1814, 2012. View at: Publisher Site | Google Scholar
  100. O. Nagano and H. Saya, “Mechanism and biological significance of CD44 cleavage,” Cancer Science, vol. 95, no. 12, pp. 930–935, 2004. View at: Publisher Site | Google Scholar
  101. K. H. Heider, M. Hofmann, E. Hors et al., “A human homologue of the rat metastasis-associated variant of CD44 is expressed in colorectal carcinomas and adenomatous polyps,” The Journal of Cell Biology, vol. 120, p. 233, 1993. View at: Google Scholar
  102. L. Wang, X. Zuo, K. Xie, and D. Wei, Methods in Molecular Biology, G. Papaccio and V. Desiderio, Eds., Humana Press Inc., 2018.
  103. Y. He, C. Xue, Y. Yu et al., “CD44 is overexpressed and correlated with tumor progression in gallbladder cancer,” Cancer Management and Research, vol. 10, pp. 3857–3865, 2018. View at: Publisher Site | Google Scholar
  104. Y. Pan, C. Han, C. Wang et al., “ADAM10 promotes pituitary adenoma cell migration by regulating cleavage of CD44 and L1,” Journal of Molecular Endocrinology, vol. 49, no. 1, pp. 21–33, 2012. View at: Publisher Site | Google Scholar
  105. I. Okamoto, H. Tsuiki, L. C. Kenyon et al., “Proteolytic cleavage of the CD44 adhesion molecule in multiple human tumors,” The American Journal of Pathology, vol. 160, no. 2, pp. 441–447, 2002. View at: Publisher Site | Google Scholar
  106. D. Masson, M. G. Denis, M. Denis et al., “Soluble CD44: quantification and molecular repartition in plasma of patients with colorectal cancer,” British Journal of Cancer, vol. 80, no. 12, pp. 1995–2000, 1999. View at: Publisher Site | Google Scholar
  107. Y.-J. Guo, G. Liu, X. Wang et al., “Potential use of soluble CD44 in serum as Indicator of tumor burden and metastasis in patients with gastric or colon cancer,” Cancer Research, vol. 54, no. 2, pp. 422–426, 1994. View at: Google Scholar
  108. W. Eisterer, O. Bechter, O. Söderberg et al., “Elevated levels of soluble CD44 are associated with advanced disease and in vitro proliferation of neoplastic lymphocytes in B-cell chronic lymphocytic leukaemia,” Leukemia Research, vol. 28, no. 10, pp. 1043–1051, 2004. View at: Publisher Site | Google Scholar
  109. E. J. Franzmann, E. P. Reategui, F. Pedroso et al., “Soluble CD44 is a potential marker for the early detection of head and neck cancer,” Cancer Epidemiology, Biomarkers & Prevention, vol. 16, no. 7, pp. 1348–1355, 2007. View at: Publisher Site | Google Scholar
  110. K. Woodson, R. Hayes, L. Wideroff, L. Villaruz, and J. Tangrea, “Hypermethylation of GSTP1, CD44, and E-cadherin genes in prostate cancer among US blacks and whites,” Prostate, vol. 55, no. 3, pp. 199–205, 2003. View at: Publisher Site | Google Scholar
  111. N. S. Verkaik, G. J. Van Steenbrugge, W. M. Van Weerden, M. J. Bussemakers, and T. H. Van Der Kwast, “Silencing of CD44 expression in prostate cancer by hypermethylation of the CD44 promoter region,” Laboratory Investigation, vol. 80, no. 8, pp. 1291–1298, 2000. View at: Publisher Site | Google Scholar
  112. T. Ahrens, J. P. Sleeman, C. M. Schempp et al., “Soluble CD44 inhibits melanoma tumor growth by blocking cell surface CD44 binding to hyaluronic acid,” Oncogene, vol. 20, no. 26, pp. 3399–3408, 2001. View at: Publisher Site | Google Scholar
  113. A. Ouhtit, B. Rizeq, H. A. Saleh, M. D. M. Rahman, and H. Zayed, “Novel CD44-downstream signaling pathways mediating breast tumor invasion,” International Journal of Biological Sciences, vol. 14, no. 13, pp. 1782–1790, 2018. View at: Publisher Site | Google Scholar
  114. A. Hill, S. McFarlane, K. Mulligan et al., “Cortactin underpins CD44-promoted invasion and adhesion of breast cancer cells to bone marrow endothelial cells,” Oncogene, vol. 25, no. 45, pp. 6079–6091, 2006. View at: Publisher Site | Google Scholar
  115. A. Ouhtit, S. Madani, I. Gupta et al., “TGF-β2: a novel target of CD44-promoted breast cancer invasion,” Journal of Cancer, vol. 4, no. 7, pp. 566–572, 2013. View at: Publisher Site | Google Scholar
  116. B. M. Ryan, N. O’Donovan, and M. J. Duffy, “Survivin: a new target for anti-cancer therapy,” Cancer Treatment Reviews, vol. 35, no. 7, pp. 553–562, 2009. View at: Publisher Site | Google Scholar
  117. E. Takahashi, O. Nagano, T. Ishimoto et al., “Tumor necrosis factor-α regulates transforming growth factor-β-dependent epithelial-mesenchymal transition by promoting hyaluronan-CD44-moesin interaction,” The Journal of Biological Chemistry, vol. 285, no. 6, pp. 4060–4073, 2010. View at: Publisher Site | Google Scholar
  118. T. Kashyap, K. K. Pramanik, N. Nath et al., “Crosstalk between Raf-MEK-ERK and PI3K-Akt-GSK3β signaling networks promotes chemoresistance, invasion/migration and stemness via expression of CD44 variants (v4 and v6) in oral cancer,” Oral Oncology, vol. 86, pp. 234–243, 2018. View at: Publisher Site | Google Scholar
  119. K. K. Pramanik, S. Nagini, A. K. Singh et al., “Glycogen synthase kinase-3β mediated regulation of matrix metalloproteinase-9 and its involvement in oral squamous cell carcinoma progression and invasion,” Cellular Oncology, vol. 41, no. 1, pp. 47–60, 2018. View at: Publisher Site | Google Scholar
  120. C. Pereira, D. Ferreira, N. Mendes, P. L. Granja, G. M. Almeida, and C. Oliveira, “Expression of CD44V6-containing isoforms influences cisplatin response in gastric cancer cells,” Cancers, vol. 12, no. 4, p. 858, 2020. View at: Publisher Site | Google Scholar
  121. J. Mo, H. W. Park, and K. Guan, “The Hippo signaling pathway in stem cell biology and cancer,” EMBO Reports, vol. 15, no. 6, pp. 642–656, 2014. View at: Publisher Site | Google Scholar
  122. Y. Xu, I. Stamenkovic, and Q. Yu, “CD44 attenuates activation of the Hippo signaling pathway and is a prime therapeutic target for glioblastoma,” Cancer Research, vol. 70, no. 6, pp. 2455–2464, 2010. View at: Publisher Site | Google Scholar
  123. O. Fedorchenko, M. Stiefelhagen, A. A. Peer-Zada et al., “CD44 regulates the apoptotic response and promotes disease development in chronic lymphocytic leukemia,” Blood, vol. 121, no. 20, pp. 4126–4136, 2013. View at: Publisher Site | Google Scholar
  124. C.-Y. Wei, M. X. Zhu, Y. W. Yang et al., “Downregulation of RNF128 activates Wnt/β-catenin signaling to induce cellular EMT and stemness via CD44 and CTTN ubiquitination in melanoma,” Journal of Hematology & Oncology, vol. 12, no. 1, p. 21, 2019. View at: Publisher Site | Google Scholar
  125. G. Chang, H. Zhang, J. Wang et al., “CD44 targets Wnt/β-catenin pathway to mediate the proliferation of K562 cells,” Cancer Cell International, vol. 13, no. 1, p. 117, 2013. View at: Publisher Site | Google Scholar
  126. Y. Sobue, N. Takahashi, Y. Ohashi et al., “Inhibition of CD44 intracellular domain production suppresses bovine articular chondrocyte de-differentiation induced by excessive mechanical stress loading,” Scientific Reports, vol. 9, no. 1, p. 14901, 2019. View at: Publisher Site | Google Scholar
  127. C. Chen, S. Zhao, A. Karnad, and J. W. Freeman, “The biology and role of CD44 in cancer progression: therapeutic implications,” Journal of Hematology & Oncology, vol. 11, no. 1, p. 64, 2018. View at: Publisher Site | Google Scholar

Copyright © 2021 Priscila Anhel Medrano-González et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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