Overexpression of FAM83A Is Associated with Poor Prognosis of Lung Adenocarcinoma

Liu, Xin; Fu, Meng; Xia, Daqing; Ji, Zimei; Hu, Nana; Leng, Zaijun; Xie, Wang; Fang, Yuan; Zhang, Junqiang

doi:https://doi.org/10.1155/2022/8767333

Journal of Oncology

On this page

Abstract Introduction Materials and Methods Results Discussion Conclusion Data Availability Ethical Approval Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Special Issue

Role of DNA Damage/Oxidative Stress as Novel Biomarkers in Tumorigenesis

View this Special Issue

Research Article | Open Access

Volume 2022 | Article ID 8767333 | https://doi.org/10.1155/2022/8767333

Overexpression of FAM83A Is Associated with Poor Prognosis of Lung Adenocarcinoma

Xin Liu,¹Meng Fu,^2,3,4Daqing Xia,²Zimei Ji,²Nana Hu,²Zaijun Leng,²Wang Xie,²Yuan Fang,²and Junqiang Zhang^1,2

Academic Editor: Muhammad Muddassir Ali

Received26 Jul 2022

Revised23 Aug 2022

Accepted15 Sept 2022

Published05 Oct 2022

Abstract

Family with sequence similarity 83, member A (FAM83A) plays an essential and fundamental role in the proliferation, progression, and apoptosis of many malignant tumors, including lung cancer. This study aimed to determine the expression pattern of FAM83A in lung adenocarcinoma (LUAD) and its correlation with the prognosis of cancer and the survival of the patients. Bioinformatics analysis, immunohistochemistry, and Western blotting were used to explore and detect the expression of FAM83A in LUAD cells. The mechanism of FAM83A in proliferation and migration was examined. The correlation between FAM83A expression and survival rate was assessed by the Kaplan-Meier and Cox regression. FAM83A expression was elevated in LUAD tissues and was related to shorter overall survival (). A significant increase in FAM83A protein was observed in the LUAD tissue (). Compared with patients with early-stage tumors (stage I-II), those with advanced stage tumors (stage III-IV) had significantly higher FAM83A expression levels (). Downregulation of FAM83A led to a reduction in cell proliferation, a decrease in migration ability, and diminished epithelial-mesenchymal transition (EMT) in the lung cancer cell lines. Overexpression of FAM83A was associated with early lymph node metastasis and poor overall survival among LUAD patients. The findings indicated that FAM83A may play a critical role in promoting the LUAD progression and thus might serve as a novel prognostic marker in LUAD.

1. Introduction

Lung cancer is one of the most common forms of cancer worldwide and also the leading cause of cancer mortalities worldwide [1]. In the recent years, the rate of incidence and mortality has significantly increased with significant gender and geographic differences. This is due to diversity in lifestyles and socioeconomic development [2]. GLOBOCAN reported approximately 2.21 million new lung cancer cases (11.4% of the total new cancer cases) and 1.80 million deaths (18.0% of the total cancer deaths) worldwide in 2020 [3]. Despite many therapies for cancer, no satisfactory clinical results have been observed because of early metastasis of tumor. Therefore, the main concern is on targeted therapies in order to increase the rate of recovery of the disease [4]. Traditional chemotherapies as the cornerstone of therapy in the first line setting in an advanced stage of lung cancer. In the past decade, significant improvements in survival rate have been observed. These improvements are due to the development of targeted therapies, i.e., epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), for lung adenocarcinoma through specific driver genes. Previous studies have demonstrated better therapeutic outcomes and fewer toxic effects via EGFR-TKIs compared with the traditional chemotherapies in patients with non-small cell lung cancer (NSCLC) and EGFR mutations [5–8]. However, resistance to EGFR-TKIs seems inevitable and limits its application in clinical practice. Despite the initial response, patients who were treated with third-generation EGFR-TKI Osimertinib would develop acquired resistance and disease progression occurred 9 to 18 months after treatment [9–11]. The patients’ disease usually deteriorates rapidly following drug resistance.

FAM83A consists of 8 genes, FAM83A-H, and is a member of the FAM83 protein family which is located on chromosome 8q24 [12]. The FAM83 family of proteins contains a highly conserved DUF1699 domain at the N-terminal, which is thought to be closely related to the biological characteristics of the tumor [13]. Previous studies indicated the overexpression of FAM83A in a variety of tumors, such as lung and breast cancers, and suggested it as a potential biomarker for cancer prognosis and a therapeutic target [14]. FAM83A could be used to predict LUAD prognosis, while FAM83B could predict the prognosis of lung squamous cell carcinoma [15]. In addition to that, FAM83A (serine and protein rich) is correlated with the poor prognosis, in the case of lung adenocarcinoma. In EMT of lung cancer, FAM83A is also involved in the Wnt/β-catenin signaling pathway [16, 17]. The public databases of bioinformatics analysis demonstrated the possible role of FAM83A overexpressed in lung cancer. Several experimental studies have reported high expression levels of FAM83A mRNA in lung cancer tissue and circulating tumor cells [18, 19]. It is also evaluated by a bioinformatics analysis that there is correlation between the expression of FAM83A and programmed death-ligand-1(PD-L1) [20]. Shi et al. proposed that long non-coding antisense RNA FAM83A-AS1 could increase FAM83A expression and promote lung cancer cell growth [21]. However, most of the conducted studies mainly focused on detecting FAM83A expression at mRNA or antisense RNA levels, rather than on protein levels. Clear that increased mRNA expression does not always indicate high protein expression, while protein is the basic and ultimate biological functional unit of genes. Consequently, to clarify the biological significance of FAM83A in lung cancer, studies on protein levels rather than mRNA levels are required. In this regard, FAM83A expression at the protein level, the role of FAM83A in LUAD biological characteristics, and its effects on the clinical and pathological characteristics of LUAD patients were investigated in the present study.

2. Materials and Methods

2.1. Collection of LUAD Tissue Samples and Clinical Information

The tissue chip contained 84 paraffin-embedded LUAD and para-cancer tissue samples of lung cancer specimens surgically removed from patients. The surgical procedures were performed in The First Affiliated Hospital of the University of Science and Technology of China (USTC) from October 2004 to August 2008. The correlation of clinical and pathological features with FAM83A expression is shown in Table 1. All experimental protocols were approved by the Institutional Research Ethics Committee of The First Affiliated Hospital of USTC (No. 2019-P-017).

2.2. Immunohistochemistry

The expression of FAM83A protein in the lung tissue was assessed by immunohistochemistry. The tissue sections were deparaffinized and rehydrated by a LEICA Autostainer (Leica ST5010, Autostainer XL, Germany) at room temperature. Antigen retrieval (AR) was performed with the citric acid solution. The tissue pieces were washed and covered with rabbit anti-FAM83A antibody (1 : 400; No: orb183622, Biorbyt, Cambridge, UK) and incubated overnight at 4°C. Then, the slides were washed with phosphate buffer saline (PBS) and incubated with secondary antibody (Envision+/HRP, Rabbit, Dako, Sweden) and diaminobenzidene (DAB) solution for 30 and 5 min at room temperature, respectively, and counterstained with hematoxylin. The stained slides were examined and quantitatively analyzed using Image J, and average optical density (AOD) was evaluated. The AOD median value (MAOD) of the detected LUAD samples was calculated. The specimen with AOD ≥ MAOD and AOD < MAOD were defined as high and low expression, respectively [17].

2.3. Cell Culture

A549, H1395, H1795, and Calu-3 cells were purchased from the American Tissue Tradition Collection (ATCC) (Manassas, VA, USA). The cells were cultured in Roswell Park Memorial Institute (RPMI) 1640 medium (HyClone, Logan, UT, Aldrich, St. Louis, MO) at 37°C in a humidified incubator with a 5% CO₂ atmosphere. The cells in the logarithmic growth phase (full to 70%-90%) were selected, shaken, and cleaned with 2 mL PBS, and then digested with trypsin at 37°C for about 1 min. The digestion was stopped by adding a complete medium, and the cell precipitation was used in subsequent experiments.

2.4. Western Blotting Assay

Western blotting was used to detect FAM83A and EMT-related protein expression in the cells. Standard procedures were performed according to the manufacturer’s instructions. Briefly, proteins in cell lysates were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and subsequently transferred onto polyvinylidene difluoride (PVDF) membranes (Millipore, Massachusetts, USA) and incubated with the following primary antibodies against FAM83A (1 : 1000; Sigma, Saint Louis, MO, USA), β-Actin (1 : 10000; Abcam, Cambridge, MA, USA), vimentin (1 : 1000; Cell Signaling Technology, Danvers, MA, USA), E-cadherin (1 : 1000; Cell Signaling Technology, Danvers, MA, USA), and Snail (1 : 1000 Cell Signaling Technology, Danvers, MA, USA). The β-actin was used as a loading control [17].

2.5. Lentivirus Transduction and Generation of Stable Cell Lines

An HIV-1-based, lentiviral expression vector designed to express a small hairpin RNA (pLVX-shRNA1) was used for cell transduction. The small hairpin RNA (shRNA) oligonucleotide sequences targeting human FAM83A gene mRNA was designed and synthesized by Huada Gene Scientific and Technological Co., Ltd. (Shenzhen, China). The target sequence of FAM83A was 5-CCGGAGGAAATTCGCTGGCCAAATCTTCAAGAGAGATTTGGCCAGCGAATTTCCTTTTTTT-3. The lentivirus with shFAM83A-gene was produced by co-transfection of 293T cells and transfected into A549 and H1795 cells. Control cells were transfected with an empty vector. Stable cells were selected with puromycin (Beyotime, Nanjing, China) after infection. Positive clones were selected for further analysis [17].

2.6. Real-Time PCR (RT-PCR)

Total RNA was extracted from cultured cells using the E.Z.N.A Total RNA Kit (R6834-02, Omega, US). Reverse transcription was carried out using Prime Script RT Reagent Kit (Takara, Japan) according to the manufacturer’s protocol. Reverse transcription polymerase chain reaction (RT-PCR) was then performed using SYBR Premix Ex Taq TM II Perfect Real-Time (DRR081A, TaKaRa, Japan) in Eppendorf Realplex 2S (Eppendorf, Germany). All primers were synthesized by Suzhou Jinweizhi Biotechnology Co., Ltd. (Suzhou, China). The primer sequences are as follows: FAM83A-F: 5- CCAGACCGTCAAGCACAACA-3, FAM83A-R: 5-GGAGCACACAAACGAACACC-3 [17].

2.7. Cell Proliferation Assay

Cell viability was assessed by a cell proliferation assay using cell counting kit-8 (CCK-8, Dojindo, Kumomoto, Japan). Briefly, the cell suspension was cultured in 96-well plates at a density of 1 × 104 cells per well. They were detected at 0, 12, 24, 48, and 72 h following the protocol. Cell growth rates were determined by measuring absorbance at 450 nm [17].

2.8. Wound-Healing Assay

Cells were cultured in a 6-well plate at a density of 1 × 10⁶ cells per well overnight. A wound was created using a 10 μL pipette tip across the center of the well. After scratching, the wells were washed three times with PBS and incubated in a CO₂ incubator at 37°C. Images were obtained immediately and 12 h after wounding. The healing of the wound surface areas was calculated and analyzed using the Image J tool (The healing areas =0-h areas – 24-h areas) [17].

2.9. Transwell Cell Assay

The cell invasion assays were performed using a Matrigel invasion chamber (pore size: 8 mm, BD Biosciences, USA) at a density of 1 × 10⁶/ml. Cells in serum-free medium were plated in the upper chamber. The chemoattractant in the lower chamber was 10% fetal bovine serum. After a 24-h incubation, the invaded cells were fixed with paraformaldehyde (PFA) and then stained with crystal violet. Finally, invaded cells were observed under an inverted microscope (Leica DMI 4000 B, Leica, Wetzlar, Germany) and manually quantified.

2.10. Bioinformatics Analysis

The study data and clinical information were provided from The Cancer Genome Atlas (TCGA) database. The University of Alabama at Birmingham cancer (UALCAN) data analysis portal (http://ualcan.path.uab.edu/analysis.html) was used to analyze the data. The Kaplan-Meier analysis was used to determine the relationship between FAM83A expression and the prognosis of the disease.

2.11. Statistical Analysis

Data was analyzed by SPSS 13.0 (Chicago, IL, USA). Correlation analysis was performed using Pearson’s chi-square test. Prognostic factor analyses were performed using univariate and multivariate Cox regression analysis. value was considered statistically significant.

3. Results

3.1. Upregulation of FAM83A in LUAD by Bioinformatics/UALCAN Analysis

UALCAN analysis of TCGA (http://ualcan.path.uab.edu/analysis.html) showed that overexpression of FAM83A occurred in NSCLC, especially LUAD (Figure 1(a)). The cluster analysis of the LUAD gene showed a significant increase in transcriptional expression of FAM83A between LUAD and the normal lung tissues (Figures 1(b) and 1(c)). Furthermore, the Kaplan-Meier analysis reported that patients with high FAM83A expression had shorter overall survival (), as shown in Figure 1(d). In conclusion, the obtained results of the TCGA database demonstrated that FAM83A overexpressed in LUAD and closely correlated with a worse prognosis.

(a)

(b)

(c)

(d)

3.2. High Expression of FAM83A in LUAD is Related to Advanced Clinical and Pathological Characteristics

Immunohistochemical staining was used to detect FAM83A protein in the LUAD tissue chip. The obtained results indicated that the FAM83A protein was dyed brown and located mostly in the cytoplasm, with a few in the nucleus (Figure 2(a)). Moreover, high expression of FAM83A in LUAD and low expression in the adjacent normal tissue were found (, Figure 2(b)). Subgroup analysis showed that stage III-IV patients had higher FAM83A expression than stage I-II patients (, Figure 2(c)). Subsequent correlation analysis suggested that FAM83A expression was correlated with clinical stages () and lymph node classifications (), but not with T classification () or metastasis classification (). Univariate and multivariate Cox regression analyses indicated that FAM83A expression was an independent prognostic factor for survival in patients with LUAD (hazard ratio: 1.745, 1.879, 95% confidential interval: 1.167–2.945, 1.075–3.321, =0.023, 0.020, respectively) (Table 2). Furthermore, the Kaplan-Meier analysis revealed that patients with high FAM83A expression had shorter overall survival (, Figure 2(d)). Consequently, the results indicated a high FAM83A expression in LUAD, which was related to advanced clinical and pathological features and poor prognosis.

(a)

(b)

(c)

(d)

Figure 2

FAM83A protein was overexpressed in LUAD and higher FAM83A expressions related to poor overall patient survival. (a) Representative hematein-eosin (HE) and immunohistochemistry (IHC) images of FAM83A expressions in adjacent normal tissues (NORMAL) and LUAD with low (LOW) and high (HIGH) FAM83A expressions. The short bar is equal to 50 microns; the long bar is equal to 100 microns. (b) The average optical density (AOD) of FAM83A in LUAD tissues and adjacent normal lung tissues. (c) AOD of FAM83A in LUAD tissues in stage I-II and stage III-IV. (d) Kaplan-Meier survival analysis showed a significant difference in 84 LUAD patients grouped by low and high FAM83A expression. , .

3.3. FAM83A Modulated Proliferation of LUAD Cells

To investigate FAM83A expression in cancer cells, its expression in several adenocarcinoma cell lines including A549, H1395, H1795, and Calu-3 cells was detected by Western blotting assay. The results showed that FAM83A expression was higher in A549 and H1795 cells and lower in H1395 and Calu-3 cells (Figures 3(a) and 3(b)). In RT-PCR, A549 and H1795 cells were treated for stable FAM83A-knockdown by shRNA (shFAM83A) and a decrease in FAM83A mRNA levels was observed (Figure 3(c)). A CCK8 cell proliferation assay revealed that FAM83A knockdown could suppress cell proliferation activity in H1795 cells. The proliferation rate of H1795-shFAM83A decreased significantly compared with the control H1795-shRNA-NC cells at each time point (0, 12, 24, 48, and 72 h) (Figure 3(e), ). In contrast, the suppression was not observed in A549 cells and it was indicated that FAM83A knockdown had no obvious effects on A549 cell proliferation (Figure 3(d), ).

(a)

(b)

(c)

(d)

(e)

Figure 3

FAM83Apromoted proliferation of LUAD cells. (a, b) Western blotting analysis showed that FAM83A levels were higher in A549 and H1795 cells. (c) The reverse transcription-polymerase chain reaction (RT-PCR) assay demonstrated that A549 and H1795 cells transfected with FAM83A lentivirus (A549/H1795-shFAM83A), showed less FAM83A RNA expressions. (d) The cell proliferation assay showed no differences between A549-shFAM83A and A549-shRNA-NC cells at each time point. (e) The cell proliferation assay showed significant differences between H1795-shFAM83A and H1795-shRNA-NC cells. , .

3.4. FAM83A Promoted LUAD Cell Migration Ability

To investigate the roles of FAM83A in cell migration, wound-healing and transwell cell assays were performed in A549 and H1795 cells. The wound-healing assay showed a significant decrease in the healing area in FAM83A knocked down cells (A549, H1795) (Figures 4(a) and 4(b)), indicating that FAM83A knockdown significantly inhibited the migration ability of A549 and H1795 cells. In addition, FAM83A knockdown in A549 and H1795 cells significantly impaired cell migration ability, as shown in the transwell cell migration assay (Figures 4(c) and 4(d)). More cells passed through the basement membrane of the transwell in FAM83A knocked-down cells, compared with in the controls. The results indicated the promotion of invasion and migration of FAM83A in the lung cancer cell.

(a)

(b)

(c)

(d)

3.5. FAM83A Induced EMT in LUAD Cells

EMT can promote tumor invasion and is a vital step during the early stage of metastasis. In this study, the expression of EMT-related markers was observed in A549 and H1795 cells. FAM83A depletion resulted in upregulation of epithelial marker E-cadherin expression and downregulation of vimentin expression as a mesenchyme marker. Furthermore, the EMT-related transcription factor Snail was downregulated when FAM83A was depleted (Figures 5(a)–5(d)). The results indicated that FAM83A depletion impaired the EMT ability of LUAD cells.

(a)

(b)

(c)

(d)

4. Discussion

In the present study, high expression of FAM83A was observed in LUAD tissues and it was noticed that FAM83A could affect tumor biological characteristics including cell proliferation, invasion, and metastasis. FAM83A overexpression was associated with advanced clinical and pathological features in LUAD patients. These findings recommended FAM83A as a LUAD oncogene and a potential biomarker for the diagnosis and prognosis of LUAD.

Similar to the results of TCGA database bioinformatics analysis, the previous studies showed an increase in FAM83A expression in LUAD patients [18, 19]. Immunohistochemical staining confirmed that FAM83A expression was increased in LUAD tissue at the protein level. The results allayed the suspicion of whether FAM83A expression was increased at the mRNA and protein levels, as mRNA expression is not always coincident with protein expression [22].

It is well known that FAM83A plays an important role in regulating cell proliferation, differentiation, and invasion. Its role in some tumors has also been well investigated. Lee et al. reported that overexpression of FAM83A in breast cancer promoted cell proliferation and invasion [23]. Chen et al. found that overexpression of FAM83A markedly increased, whereas inhibition of FAM83A decreased cell proliferation in an in-vivo mouse model of pancreatic cancer [24]. The phosphorylation of FAM83A, downstream of EGFR, and upstream of ERK might activate the PI3K/AKT and MAPK signaling pathways, promoting the proliferation, differentiation, apoptosis, and invasion of cells [25, 26]. In the present study, depletion of FAM83A expression inhibited the proliferation, migration, and invasion of lung adenocarcinoma cells. Interestingly, the proliferation capacity of A549 cells exhibited a significant decreasing trend after FAM83A depletion. A possible reason might be a rather limited FAM83A overexpression in A549 cells compared to the H1795 cells. Consequently, the effectiveness of FAM83A knockdown by shRNA remained obscure. A recent study that detected FAM83A expression in nine adenocarcinoma cell lines including A549 cells was detected by the study of Zhou et al. High expression of FAM83A in some cell lines and relatively low expression in A549 cells were observed [27].

EMT is an essential process that promotes adherent epithelial cell movement. EMT can enhance cell mobility and promote tumor progression, and affect cancer features, especially invasion and metastasis [28–31]. In the current study, it was found that FAM83A depletion resulted in the absence of mesenchymal markers, indicating that FAM83A was involved in LUAD EMT processes. In addition, it was observed that under-expression of FAM83A reduced Snail expression, suggesting that FAM83A might regulate the EMT phenotype by inhibiting Snail expressions. Previous studies have shown that constitutive activation of the PI3K/AKT signaling cascade was closely correlated with Snail upregulation and diverse tumor cell metastasis [32–37]. Therefore, investigating whether FAM83A activates Snail and regulates EMT through the PI3K/AKT pathway is worth further studies.

The clinical significance of FAM83A in some cancer types such as breast cancer has been well studied [23]. There is convincing evidence that FAM83A is also related to the prognosis of lung cancer [15]. In the present study, the bioinformatics analysis demonstrated that overexpression of FAM83A was correlated with poor patient survival. Furthermore, immunohistochemical experiments revealed an increase in staining of FAM83A expression in stage III and IV patients, where FAM83A overexpression was positively associated with disease stage and lymph node classification. The results indicated that high FAM83A expression was related to advanced clinical and pathological LUAD characteristics. In breast cancer, FAM83A regulates the proliferation and invasion of cancer cells through the PI3K/AKT pathway. Inhibition of related kinases on this pathway can block the regulator effects of FAM83A on breast cancer [23, 37].

In the present study, the molecular mechanism of FAM83A in the regulation of proliferation, invasion, and EMT was evaluated. It is not clear whether the PI3K/AKT pathways are similarly involved in the regulatory mechanism of FAM83A in LUAD. As well as further studies are required to identify novel drug targets which may provide new therapeutic targets for LUAD. Therefore, it is suggested that these factors must be investigated and should be considered in future studies.

5. Conclusion

According to the results, at advanced stages of cancer, transcriptional expression as well as the protein level of FAM83A is increased in lung adenocarcinoma. Due to depletion of FAM83A, there is an increased expression of various types of markers, i.e., epithelial and mesenchyme. This overexpression shown the poor prognosis of FAM83A in lung cancer. In the future, FAM83A might be a potential new target for molecular targeted therapy of patients to its strong association with prognosis and expression of the disease.

Data Availability

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Ethical Approval

All experimental protocols were approved by the Institutional Research Ethics Committee of The First Affiliated Hospital of USTC (No. 2019-P-017).

Conflicts of Interest

The authors declare that they have no competing interests.

Authors’ Contributions

JZ and XL contributed to the conceptualization; JZ and MF contributed to the methodology; XL and MF were responsible for the software; DX, ZJ, and YF contributed to the validation; XL and WX contributed to the formal analysis; XL contributed to the investigation; XL and JZ were responsible for the resources; XL and MF contributed to the data curation; ZJ and XL contributed to the writing—original draft preparation; MF and ZJ contributed to the writing—review and editing; ZL, ZJ, and XL contributed to the visualization; ZJ contributed to the supervision; ZJ and NH contributed to the project administration. All authors have read and agreed to the published version of the manuscript. Xin Liu and Meng Fu are co-first authors and contributed equally to this work.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (82000082), the Provincial Natural Science Foundation of Anhui (2008085QH353), and the Fundamental Research Funds for the Central University (WK9110000124).

References

H. Brody, “Lung cancer,” Nature, vol. 587, no. 7834, p. S7, 2020.
View at: Publisher Site | Google Scholar
S. Gao, N. Li, S. Wang et al., “Lung cancer in people’s Republic of China,” Journal of Thoracic Oncology, vol. 15, no. 10, pp. 1567–1576, 2020.
View at: Publisher Site | Google Scholar
H. Sung, J. Ferlay, R. L. Siegel et al., “Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries,” CA: a Cancer Journal for Clinicians, vol. 71, no. 3, pp. 209–249, 2021.
View at: Publisher Site | Google Scholar
H. Hu, F. Wang, M. Wang et al., “FAM83A is amplified and promotes tumorigenicity in non-small cell lung cancer via ERK and PI3K/Akt/mTOR pathways,” International Journal of Medical Sciences, vol. 17, no. 6, pp. 807–814, 2020.
View at: Publisher Site | Google Scholar
T. Mitsudomi, S. Morita, Y. Yatabe et al., “Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial,” The Lancet Oncology, vol. 11, no. 2, pp. 121–128, 2010.
View at: Publisher Site | Google Scholar
M. Maemondo, A. Inoue, K. Kobayashi et al., “Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR,” The New England Journal of Medicine, vol. 362, no. 25, pp. 2380–2388, 2010.
View at: Publisher Site | Google Scholar
Y. L. Wu, C. Zhou, C. K. Liam et al., “First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study^†,” Annals of Oncology, vol. 26, no. 9, pp. 1883–1889, 2015.
View at: Publisher Site | Google Scholar
J. Y. Han, K. Park, S. W. Kim et al., “First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung,” Journal of Clinical Oncology, vol. 30, no. 10, pp. 1122–1128, 2012.
View at: Publisher Site | Google Scholar
G. R. Oxnard, M. E. Arcila, C. S. Sima et al., “Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation,” Clinical Cancer Research, vol. 17, no. 6, pp. 1616–1622, 2011.
View at: Publisher Site | Google Scholar
C. Zhou, Y. L. Wu, G. Chen et al., “Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study,” The Lancet Oncology, vol. 12, no. 8, pp. 735–742, 2011.
View at: Publisher Site | Google Scholar
K. S. Thress, C. P. Paweletz, E. Felip et al., “Acquired EGFR C797S mutation mediates resistance to AZD9291 in non -small cell lung cancer harboring EGFR T790M,” Nature Medicine, vol. 21, no. 6, pp. 560–562, 2015.
View at: Publisher Site | Google Scholar
C. A. Bartel, N. Parameswaran, R. Cipriano, and M. W. Jackson, “FAM83 proteins: fostering new interactions to drive oncogenic signaling and therapeutic resistance,” Oncotarget, vol. 7, no. 32, pp. 52597–52612, 2016.
View at: Publisher Site | Google Scholar
L. J. Fulcher, P. Bozatzi, T. Tachie-Menson et al., “The DUF1669 domain of FAM83 family proteins anchor casein kinase 1 isoforms,” Science Signaling, vol. 11, no. 531, 2018.
View at: Publisher Site | Google Scholar
A. M. Snijders, S. Y. Lee, B. Hang, W. Hao, M. J. Bissell, and J. H. Mao, “FAM83 family oncogenes are broadly involved in human cancers: an integrative multi-omics approach,” Molecular Oncology, vol. 11, no. 2, pp. 167–179, 2017.
View at: Publisher Site | Google Scholar
S. Richtmann, D. Wilkens, A. Warth et al., “FAM83A and FAM83B as prognostic biomarkers and potential new therapeutic targets in NSCLC,” Cancers, vol. 11, no. 5, 2019.
View at: Publisher Site | Google Scholar
Y. W. Zheng, Z. H. Li, L. Lei et al., “FAM83A promotes lung cancer progression by regulating the Wnt and Hippo signaling pathways and indicates poor prognosis,” Frontiers in Oncology, vol. 5, no. 10, p. 180, 2020.
View at: Publisher Site | Google Scholar
H. Ji, H. Song, Z. Wang et al., “FAM83A promotes proliferation and metastasis via Wnt/β-catenin signaling in head neck squamous cell carcinoma,” Journal of Translational Medicine, vol. 19, no. 1, pp. 1–3, 2021.
View at: Publisher Site | Google Scholar
L. Liu, G. Liao, P. He et al., “Detection of circulating cancer cells in lung cancer patients with a panel of marker genes,” Biochemical and Biophysical Research Communications, vol. 372, no. 4, pp. 756–760, 2008.
View at: Publisher Site | Google Scholar
Y. Li, X. Dong, Y. Yin et al., “BJ-TSA-9, a novel human tumor-specific gene, has potential as a biomarker of lung cancer,” Neoplasia, vol. 7, no. 12, pp. 1073–1080, 2005.
View at: Publisher Site | Google Scholar
Z. Fengrui, W. Xin, L. Fang, M. Qingwei, and Y. Yan, “PD-L1 expression via ERK signaling and FAM83A/PD-L1 co-expression correlates with poor prognosis in lung adenocarcinoma,” International Journal of Clinical Oncology, vol. 25, pp. 1612–1623, 2020.
View at: Google Scholar
R. Shi, Z. Jiao, A. Yu, and T. Wang, “Long noncoding antisense RNA FAM83A-AS1 promotes lung cancer cell progression by increasing FAM83A,” Journal of Cellular Biochemistry, vol. 120, no. 6, pp. 10505–10512, 2019.
View at: Publisher Site | Google Scholar
J. Li, W. Zhao, R. Akbani et al., “Characterization of human cancer cell lines by reverse-phase protein arrays,” Cancer Cell, vol. 31, no. 2, pp. 225–239, 2017.
View at: Publisher Site | Google Scholar
S. Y. Lee, R. Meier, S. Furuta et al., “FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice,” The Journal of Clinical Investigation, vol. 122, no. 9, pp. 3211–3220, 2012.
View at: Publisher Site | Google Scholar
S. Chen, J. Huang, Z. Liu, Q. Liang, N. Zhang, and Y. Jin, “FAM83A is amplified and promotes cancer stem cell-like traits and chemoresistance in pancreatic cancer,” Oncogenesis, vol. 6, no. 3, p. 300, 2017.
View at: Publisher Site | Google Scholar
P. J. Liu, Y. H. Chen, K. W. Tsai et al., “Involvement of micro RNA-1-FAM83A axis dysfunction in the growth and motility of lung cancer cells,” International Journal of Molecular Sciences, vol. 21, no. 22, pp. 1–17, 2020.
View at: Publisher Site | Google Scholar
C. A. Bartel, M. W. Jackson, and M. W. Jackson, “HER2-positive breast cancer cells expressing elevated FAM83A are sensitive to FAM83A loss,” PLoS One, vol. 12, no. 5, 2017.
View at: Publisher Site | Google Scholar
F. Zhou, J. Geng, S. Xu et al., “FAM83A signaling induces epithelial-mesenchymal transition by the PI3K/AKT/Snail pathway in NSCLC,” Aging (Albany NY), vol. 11, no. 16, pp. 6069–6088, 2019.
View at: Publisher Site | Google Scholar
D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, pp. 646–674, 2011.
View at: Publisher Site | Google Scholar
F. Bunz, “EMT and back again: visualizing the dynamic phenotypes of metastasis,” Cancer Research, vol. 80, no. 2, pp. 153–155, 2020.
View at: Publisher Site | Google Scholar
I. Pastushenko and C. Blanpain, “EMT transition states during tumor progression and metastasis,” Trends in Cell Biology, vol. 29, no. 3, pp. 212–226, 2019.
View at: Publisher Site | Google Scholar
N. M. Aiello and Y. Kang, “Context-dependent EMT programs in cancer metastasis,” The Journal of Experimental Medicine, vol. 216, no. 5, pp. 1016–1026, 2019.
View at: Publisher Site | Google Scholar
X. H. F. Zhang, X. Jin, S. Malladi et al., “Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma,” Cell, vol. 154, no. 5, pp. 1060–1073, 2013.
View at: Publisher Site | Google Scholar
M. J. Barberà, I. Puig, D. Domínguez et al., “Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells,” Oncogene, vol. 23, no. 44, pp. 7345–7354, 2004.
View at: Publisher Site | Google Scholar
W. Wen, J. Ding, W. Sun et al., “Cyclin G1-mediated epithelial-mesenchymal transition via phosphoinositide 3-kinase/Akt signaling facilitates liver cancer progression,” Hepatology, vol. 55, no. 6, pp. 1787–1798, 2012.
View at: Publisher Site | Google Scholar
A. W. Ke, G. M. Shi, J. Zhou et al., “CD151 amplifies signaling by integrin α6β1 to PI3K and induces the epithelial–mesenchymal transition in HCC cells,” Gastroenterology, vol. 140, no. 5, pp. 1629–1641.e15, 2011.
View at: Publisher Site | Google Scholar
H. Hamidi and J. Ivaska, “Every step of the way: integrins in cancer progression and metastasis,” Nature Reviews. Cancer, vol. 18, no. 9, pp. 533–548, 2018.
View at: Publisher Site | Google Scholar
S. Grant, “FAM83A and FAM83B: candidate oncogenes and TKI resistance mediators,” The Journal of Clinical Investigation, vol. 122, pp. 3048–3051, 2012.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2022 Xin Liu 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.

PDF Download Citation

Download other formats

Order printed copies

Views

310

Downloads

463

Citations