Table of Contents Author Guidelines Submit a Manuscript
Analytical Cellular Pathology
Volume 2019, Article ID 9419072, 7 pages
https://doi.org/10.1155/2019/9419072
Review Article

The State of the Art on Blood MicroRNAs in Pancreatic Ductal Adenocarcinoma

1Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
2Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing 100050, China
3National Clinical Research Center for Digestive Diseases, Beijing 100050, China

Correspondence should be addressed to Peng Li; nc.ude.umcc@gnepil

Received 31 July 2019; Accepted 3 September 2019; Published 10 September 2019

Academic Editor: Silvia Cantara

Copyright © 2019 Zhuqing Gao 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.

Abstract

Despite enormous advances being made in diagnosis and therapeutic interventions, pancreatic ductal adenocarcinoma (PDAC) is still recognized as one of the most lethal malignancies. Early diagnosis and timely curative surgery can markedly improve the prognosis; hence, there is an unmet necessity to explore efficient biomarkers for patients’ benefit. Recently, blood miRNAs (miRNAs) have been reported to be a novel biomarker in human cancers. Part of it is selectively packaged by plasma exosomes released from cells via exocytosis and is highly sensitive to changes in the tumor microenvironment. Furthermore, due to less invasiveness and technical availability, miRNA-based liquid biopsy holds promise for further wide usage. Therefore, this review is aimed at presenting an update on the association between blood miRNAs and the biology of PDAC, then discussing its clinical utilization further.

1. Introduction

Pancreatic ductal adenocarcinoma (PDAC) remains the fourth leading cause of cancer-related death worldwide [1]. It has extremely poor prognosis characterized by only 18% one-year survival rate for all stages, partly due to its aggressive tumor biology such as intrinsic chemoresistance and high metastatic capacity. The lack of alarming symptoms in the early phase of PDAC makes the early diagnosis difficult; thus, only 20% of patients are suitable for potentially curative surgical resection [2]. Even when treated with surgery, the five-year survival rate for patients with node-negative and node-positive can only reach 25-30% and 10%, respectively [3]. For the majority of PDAC patients, current first-line therapy such as chemotherapy fails to improve the prognosis significantly [4]. Considering the disappointing diagnostic approaches and the poor prognosis of PDAC, it is necessary to develop tumor markers for screening, postoperative surveillance, and predicting the prognosis of curative resection. However, no biomarkers in routine practice have proven to be a powerful and widely accepted approach for large-scale screening and surveillance. For instance, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA-199) as traditional biomarkers are neither sensitive nor specific for early screening and predicting prognosis [5, 6]. The higher level of those biomarkers indicate the occurrence not only of PDAC but also of other malignancies such as colorectal carcinoma and benign lesions like pancreatitis, cirrhosis, and choledocholithiasis [7]. Moreover, many commercial kits available have not reached a widely accepted standard, and its fluctuation based on the bilirubin level limited its usage as a stand-alone test for screening and predicting prognosis [8, 9].

miRNAs have been accumulating for years [10]. They belong to a class of small noncoding RNAs (18-25 nucleotides) and can stabilize messenger RNA (mRNA) transcripts by inhibiting the translation process or cleaving their target mRNA [1013]. While only covering 3% in the human genome, they can affect the expression level of 20-30% protein-coding genes [14, 15], which play a pivotal role in cell growth, differentiation, and apoptosis. In recent decades, the altered expression of miRNAs has been reported to have a carcinogenic or tumor-suppressing role in malignancies. The aberrant expression of miRNAs can be informative and be an indirect predictor in the development of differentiated solid tumors. Moreover, evidence showed that a substantial proportion of miRNAs abnormally expressed in PDAC. Thus, many studies were carried out to investigate whether this type of biomarkers can be a potential quantified tool for early diagnosis and prognosis prediction. miRNAs can remain stable in form and can be quantified in tissues, plasma, stool, pancreatic juice, and other fluids. Among these, the blood assay of miRNAs could potentially be an efficient regular test for the benefit of high-risk individuals, due to its less invasiveness and technology availability.

This review is aimed at presenting the evidence of blood miRNAs on early diagnosis, predictive treatment, and confirmation of postoperative prognosis in PDAC patients.

2. miRNAs in the Blood

Accumulating studies have reported the miRNA expression in the whole blood or peripheral blood mononuclear cell (PBMCs) [1631] (Table 1). A study comparing the miRNA expression between healthy subjects and PDAC patients demonstrated that levels of miRNA-10b, miRNA-21, miRNA-30c, and miRNA-181a were significantly higher, whereas the expression of miRNA-let7a was lower in PDAC patients compared with controls [32]. In another study, the lower level of miRNA-155 and miRNA-196a and the increased expression of miRNA-17-5p and miRNA-21 could be observed in the subsets of PDAC patients. Interestingly, altered expression of miRNA-17-5p was linked to tumor metastasis, which could significantly affect the prognosis of patients [33].

Table 1: MicroRNAs for the early detection of pancreatic cancer.

Many investigators have formulated scenarios to explore how miRNAs can survive from endogenous ribonucleases in the blood. Currently, it is widely accepted that miRNAs can circulate in blood selectively packaged by lipoprotein vesicles, such as exosomes [3436]. As extracellular vesicles, exosomes (30-150 nm) are secreted by all living cells via exocytosis. The exact function and mechanism of exosomes remained unknown. The current hypothesis uncovered that it may function to expel excess and nonfunctional cellular constituents. In addition, exosomes would recycle cell surface protein and modulate signaling [37, 38]. They contain the tissue-specific protein that can package RNA (mRNA and miRNA), then transport to other cells in circulating fluid. A previous study reported that the concentration of exosomes would be much higher in the blood of cancer patients than in their healthy counterparts [39]. It was also confirmed that exosome-encapsulated miRNAs can be detected in the serum of PDAC patients. The levels of miRNA-1246, miRNA-4644, miRNA-3976, and miRNA-4306 in PDAC were markedly upregulated in 83% of serum exosomes compared to control groups [40]. Another study reported that elevated levels of exosome-encapsulated miRNA-10b, miRNA-21, miRNA-30c, and miRNA-181a and decreased miRNA-let7a readily differentiate PDAC from normal control and chronic pancreatitis samples. Besides, elevated exosomal miRNA levels decreased after PDAC resection [34]. These studies suggest that serum-derived exosome miRNAs might be potential candidate biomarkers for patients with early-stage PDAC [34, 4044] (Table 2).

Table 2: Exosomal microRNA in pancreatic cancer patients.

3. Blood miRNAs in Diagnosis of PDAC

Early diagnosis and timely surgery have been reported to elicit better prognosis that the 5-year survival rate can reach 50% for PDAC in stage I [45, 46]. However, it remains an elusive goal, considering that laboratory findings did not show efficiency or high sensitivity during routine practice. Enormous endeavors have been devoted to investigating the association between miRNA expression and the diagnosis of malignancies. The goal for screening high-risk individuals has also contributed to identifying promising biomarkers for PDAC.

Tissue miRNAs have showed good performance in evaluating prognosis and survival after tumor resection. However, the invasiveness in collecting tissues and the lack of available samples have limited its usage. Inconsistent with tissues, circulating miRNAs presenting in the serum, plasma, or PBMCs can be isolated directly with minimal invasion. They are also technically easier to detect, more abundant, and resistant to the degradation of RNase. Attempts to assess the efficiency of blood miRNAs solely or in conjunction with CA19-9 have yielded various results [20, 24, 26, 4753]. According to a study performed by Li et al., serum levels of miRNA-200a/200b were quantified in a series of 45 PDAC patients, 11 chronic pancreatitis patients, and 32 healthy counterparts. It can be observed that the elevation of miRNA-200a and miRNA-200b had a sensitivity of 84.4% and 71.1% and a specificity of 87.5% and 96.9%, respectively [53]. miRNA-16a and miRNA-196a combined with CA19-9 showed a promising result in the detection of PDAC in stage I, indicating that miRNA-16a and miRNA-196a might be used for peripheral biomarkers of PDAC [20]. Recently, a large-scale clinical trial recruiting 197 PDAC cases and 158 controls has been conducted on a miRNA panel including miRNA-20a, miRNA-21, miRNA-24, miRNA-25, miRNA-99a, miRNA-185, and miRNA-191. The overall accuracy was 86.8% compared with 76% for CA19-9. Of the stage I PDAC patients, the specificity of this seven-miRNA panel was 96.2% compared with CA199 46.2%. This panel was observed to be a potential biomarker of early diagnosis and distinguishing PDAC from chronic pancreatitis. Moreover, miRNA-1290 was also observed to distinguish early-stage PDAC patients from the targeted population [54]. The expression of miRNAs has also been evaluated in PDAC, intraductal papillary mucinous neoplasm (IPMN), and healthy subjects. In a study including 32 patients with PDAC, 12 patients with IPMN, and 30 healthy controls, the expression levels of plasma miRNA-483-3p and miRNA-21 in PDAC especially in advanced metastatic cases were significantly higher than that of healthy controls. Interestingly, the expression of plasma miRNA-483-3p in PDAC patients was also significantly higher than that in IPMN patients, which could be used to distinguish PDAC and IPMN [55].

These research focusing on detecting the role of blood miRNA in the diagnosis of PDAC has added to the evidence that it may be efficiently used for screening in routine practice in the future.

4. miRNA in the Treatment of PDAC

For the majority of patients in the advanced stage, chemotherapy may be the only therapy with palliative intent. However, high resistance to chemotherapy partially contributed to the poor prognosis. To date, it is accepted that PDAC cells that survived the initial chemotherapy can harbor a secondary generation of cells that can be resistant to therapy. Some studies have reported that the expression of specific miRNAs may affect characteristics of cancer stem cells. miRNA-21 has been investigated to be a potential marker of poor prognosis in PDAC. Its expression was positively correlated with the IC50 of gemcitabine. The overexpression of miRNA-21 induced by transfection was associated with enhancing proliferation, invasion, and suppressing apoptosis in PDAC cell lines [16]. Also, pancreatic cancer cells with lower miRNA-21 expression can confer higher sensitivity to 5-fluorouracil. Lately, Zhu et al. showed that transfection with miRNA-21 could increase the expression of PTEN and enhance the effect of the gemcitabine-induced cell apoptosis [56]. Moreover, the correlation between miRNA-21 and matrix metalloproteinase-2/9 as well as vascular endothelial growth factor (VEGF) was assessed in another study. A postulation can be made that miRNA-21 may also play a role in angiogenesis [57]. A further large-scale clinical trial could be carried out in a targeted population with a tendency for gemcitabine-resistance.

Apart from miRNA-21, other miRNAs have also been observed to be potential indicators in therapy. miRNA-200 was reported to be a promising tumor suppressor which plays a pivotal part in cancer metastases. It was also involved in chemoresistance. It was found that supplementation with curcumin, a dominant component of Indian spice, could upregulate miRNA-200 and downregulate miRNA-21 [58]. In another study by Zhang et al., miRNA-214 was reported to downregulate ING4 to promote the survival of PDAC cells in gemcitabine-resistance. Also, miRNA-15a can suppress the production of tumor cells in PDAC cells. Moreover, a high level of miRNA-15a inhibiting WNT3a and FGF7 expression correlates with the reduced PDAC cell viability [59].

Recently, the efficiency of nanoformulations, in which nanoparticles are combined with miRNA, has been evaluated both in the PDAC cell culture or in animal models, throwing new light on miRNA treatment in pancreatic cancer. In a study by Arora et al. [60], the level of miRNA-150 was lower in the majority of pancreatic cancer patients. Thus, poly(D, L-lactide-co-glycolide)- (PLGA-) based nanoformulations of miRNA-150 (miRNA-150-NF) were developed. Treatment with miRNA-150-NF efficiently promoted the production of the miRNA-mimic in PDAC cells and significantly downregulated the expression of its target gene, MUC4. The inhibition of MUC4 further suppressed the production of its interacting partner HER2 and inhibited its downstream signaling. Finally, the proliferation of PDAC cells was observed to be significantly inhibited. In another study, the researchers delivered the established system with two miRNAs (miRNA-34a and miRNA-143/145) encapsulated to the subcutaneous transplanted tumor cells of mice by intravenous injection. It was observed that the system can enhance the apoptosis of tumor cells and suppressed the cell proliferation. miRNA-34a is a component of the p53 transcriptional network and regulates the survival of cancer stem cells. miRNA-143/145 inhibits the expression of Kirsten rat sarcoma viral oncogene (KRAS2) and its downstream effector Ras-responsive element binding protein-1 (RREB1) [61]. Both of those miRNAs could contribute to the tumor-suppressing effect of the established system [61].

The endeavors have always been contributing to the miRNA therapy for PDAC in these years. It has shown promising results both in vivo and in vitro. In the future, its efficiency in PDAC patients needs to be validated in preclinical studies.

5. miRNA in the Prognosis of PDAC

As a malignancy harboring poor prognosis, it is pivotal to predict its activity when considering more precise therapy. Recently, many specific miRNA patterns have been reported to provide evidence for worse prognosis and more aggressive activity. In an analysis that enrolled 1525 patients, higher expression of miRNA-21 was observed to be correlated with a shorter significant disease-free survival. Similarly, upregulation of miRNA-155, miRNA-203, miRNA-222, and miRNA-10b and downregulation of miRNA-34a and miRNA-183 showed a worse prognosis and correlated with tumor grade, stage, and metastasis. Aberrant expression of these panels are independent predictors of worse prognosis of PDAC patients [62]. Another recent study found that high expression of miRNA-142-5p and miRNA-204 correlated with better survival. Collectively, these studies proved miRNAs as a novel biomarker for predicting prognosis [23].

Moreover, the association between 494 miRNAs and overall survival was analyzed by the Cancer Genome Atlas (TCGA). Five miRNAs significantly correlated with overall survival were miRNA-1301, miRNA-125a, miRNA-376c, miRNA-328, and miRNA-376b, which can be used as independent prognostic factors for PDAC [63]. In a study that recruited 104 patients with PDAC, three subtypes of PDAC associated with prognosis were identified by microarray analysis of 1733 miRNA expression profiles. Among 19 characteristic miRNAs, miRNA-106b-star, miRNA-324-3p, and miRNA-615 were associated with the p53 classical pathway, while miRNA-324, miRNA-145-5p, miRNA-26b-5p, and miRNA-574-3p were associated with the Cox-2 central pathway [64]. The recurrence of malignancies might be also assessed by miRNAs. Morimura et.al found that the high serum level of miRNA-18a in PDAC patients was cut off after resection of the tumors. In one case of recurrence after resection, miRNA-18a was found to be elevated. Such biomarkers can be investigated further to screen recurring tumors.

6. Conclusion

Current tumor biomarkers (CA19-9, CEA) in clinical practice have improved the screening for PDAC. However, this kind of implementation shows low sensitivity and specificity in some circumstances. As a novel molecular marker, blood miRNAs not only have the advantages of noninvasiveness and higher accuracy but also improve the evaluation of tumor classification, metastasis, curative effect, and recurrence. However, it is an urgent problem to find a detection method with high sensitivity, technically easier access, and lower cost due to the low expression level of miRNA in serum. What is more, a sole miRNA is often insufficiently specific. Thus, it is expected to significantly improve the accuracy of the diagnosis if a panel of miRNAs can be used. As an emerging tumor molecular marker category, blood miRNA might be a promising and novel tool in the clinical diagnosis and treatment of PDAC.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Zhuqing Gao and Wei Jiang contributed equally to this work.

References

  1. R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, 2017,” CA: A Cancer Journal for Clinicians, vol. 67, no. 1, pp. 7–30, 2017. View at Publisher · View at Google Scholar · View at Scopus
  2. D. Li, K. Xie, R. Wolff, and J. L. Abbruzzese, “Pancreatic cancer,” The Lancet, vol. 363, no. 9414, pp. 1049–1057, 2004. View at Publisher · View at Google Scholar · View at Scopus
  3. E. L. Fogel, S. Shahda, K. Sandrasegaran et al., “A multidisciplinary approach to pancreas cancer in 2016: a review,” The American Journal of Gastroenterology, vol. 112, no. 4, pp. 537–554, 2017. View at Publisher · View at Google Scholar · View at Scopus
  4. T. Kamisawa, L. D. Wood, T. Itoi, and K. Takaori, “Pancreatic cancer,” The Lancet, vol. 388, no. 10039, pp. 73–85, 2016. View at Publisher · View at Google Scholar · View at Scopus
  5. E. P. Dimagno, H. A. Reber, and M. A. Tempero, “American gastroenterological association medical position statement: epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma,” Gastroenterology, vol. 117, no. 6, pp. 1463-1464, 1999. View at Publisher · View at Google Scholar · View at Scopus
  6. R. Lamerz, “Role of tumour markers, cytogenetics,” Annals of Oncology, vol. 10, Supplement 4, pp. S145–S149, 1999. View at Publisher · View at Google Scholar · View at Scopus
  7. U. K. Ballehaninna and R. S. Chamberlain, “The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: an evidence based appraisal,” Journal of Gastrointestinal Oncology, vol. 3, no. 2, pp. 105–119, 2012. View at Publisher · View at Google Scholar · View at Scopus
  8. J. R. Bergquist, C. A. Puig, C. R. Shubert et al., “Carbohydrate antigen 19-9 elevation in anatomically resectable, early stage pancreatic cancer is independently associated with decreased overall survival and an indication for neoadjuvant therapy: a National Cancer Database study,” Journal of the American College of Surgeons, vol. 223, no. 1, pp. 52–65, 2016. View at Publisher · View at Google Scholar · View at Scopus
  9. S. Scara, P. Bottoni, and R. Scatena, “CA 19-9: biochemical and clinical aspects,” in Advances in Cancer Biomarkers, R. Scatena, Ed., vol. 867 of Advances in Experimental Medicine and Biology, pp. 247–260, Springer, Dordrecht, 2015. View at Publisher · View at Google Scholar · View at Scopus
  10. S. Sethi, D. Kong, S. Land, G. Dyson, W. A. Sakr, and F. H. Sarkar, “Comprehensive molecular oncogenomic profiling and miRNA analysis of prostate cancer,” Journal of Translational Research, vol. 5, no. 2, pp. 200–211, 2013. View at Google Scholar
  11. A. Sethi and L. M. Sholl, “Emerging evidence for microRNAs as regulators of cancer stem cells,” Cancers, vol. 3, no. 4, pp. 3957–3971, 2011. View at Publisher · View at Google Scholar · View at Scopus
  12. A. Keller, P. Leidinger, A. Borries et al., “miRNAs in lung cancer - studying complex fingerprints in patient’s blood cells by microarray experiments,” BMC Cancer, vol. 9, no. 1, p. 353, 2009. View at Publisher · View at Google Scholar · View at Scopus
  13. O. Hassan, A. Ahmad, S. Sethi, and F. H. Sarkar, “Recent updates on the role of microRNAs in prostate cancer,” Journal of Hematology & Oncology, vol. 5, no. 1, p. 9, 2012. View at Publisher · View at Google Scholar · View at Scopus
  14. I. Bentwich, A. Avniel, Y. Karov et al., “Identification of hundreds of conserved and nonconserved human microRNAs,” Nature Genetics, vol. 37, no. 7, pp. 766–770, 2005. View at Publisher · View at Google Scholar · View at Scopus
  15. R. W. Carthew, “Gene regulation by microRNAs,” Current Opinion in Genetics & Development, vol. 16, no. 2, pp. 203–208, 2006. View at Publisher · View at Google Scholar · View at Scopus
  16. E. Giovannetti, N. Funel, G. J. Peters et al., “MicroRNA-21 in pancreatic cancer: correlation with clinical outcome and pharmacologic aspects underlying its role in the modulation of gemcitabine activity,” Cancer Research, vol. 70, no. 11, pp. 4528–4538, 2010. View at Publisher · View at Google Scholar · View at Scopus
  17. I. Bhatti, A. Lee, V. James et al., “Knockdown of microRNA-21 inhibits proliferation and increases cell death by targeting programmed cell death 4 (PDCD4) in pancreatic ductal adenocarcinoma,” Journal of Gastrointestinal Surgery, vol. 15, no. 1, pp. 199–208, 2011. View at Publisher · View at Google Scholar · View at Scopus
  18. Y. Nagao, M. Hisaoka, A. Matsuyama et al., “Association of microRNA-21 expression with its targets, PDCD4 and TIMP3, in pancreatic ductal adenocarcinoma,” Modern Pathology, vol. 25, no. 1, pp. 112–121, 2012. View at Publisher · View at Google Scholar · View at Scopus
  19. J. K. Park, E. J. Lee, C. Esau, and T. D. Schmittgen, “Antisense inhibition of microRNA-21 or -221 arrests cell cycle, induces apoptosis, and sensitizes the effects of gemcitabine in pancreatic adenocarcinoma,” Pancreas, vol. 38, no. 7, pp. e190–e199, 2009. View at Publisher · View at Google Scholar · View at Scopus
  20. J. Liu, J. Gao, Y. du et al., “Combination of plasma microRNAs with serum CA19-9 for early detection of pancreatic cancer,” International Journal of Cancer, vol. 131, no. 3, pp. 683–691, 2012. View at Publisher · View at Google Scholar · View at Scopus
  21. A. Drakaki and D. Iliopoulos, “MicroRNA-gene signaling pathways in pancreatic cancer,” Biometrical Journal, vol. 36, no. 5, pp. 200–208, 2013. View at Publisher · View at Google Scholar · View at Scopus
  22. O. W. Rokhlin, V. S. Scheinker, A. F. Taghiyev, D. Bumcrot, R. A. Glover, and M. B. Cohen, “MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer,” Cancer Biology & Therapy, vol. 7, no. 8, pp. 1288–1296, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. Y. Li, T. G. VandenBoom, D. Kong et al., “Upregulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells,” Cancer Research, vol. 69, no. 16, pp. 6704–6712, 2009. View at Publisher · View at Google Scholar · View at Scopus
  24. T. Kawaguchi, S. Komatsu, D. Ichikawa et al., “Clinical impact of circulating miR-221 in plasma of patients with pancreatic cancer,” British Journal of Cancer, vol. 108, no. 2, pp. 361–369, 2013. View at Publisher · View at Google Scholar · View at Scopus
  25. O. A. Kent, R. R. Chivukula, M. Mullendore et al., “Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway,” Genes & Development, vol. 24, no. 24, pp. 2754–2759, 2010. View at Publisher · View at Google Scholar · View at Scopus
  26. G. A. Cote, J. A. Gore, S. D. McElyea et al., “A pilot study to develop a diagnostic test for pancreatic ductal adenocarcinoma based on differential expression of select miRNA in plasma and bile,” American Journal of Gastroenterology, vol. 109, no. 12, pp. 1942–1952, 2014. View at Publisher · View at Google Scholar · View at Scopus
  27. S. Guo, X. Xu, Y. Tang et al., “miR-15a inhibits cell proliferation and epithelial to mesenchymal transition in pancreatic ductal adenocarcinoma by down-regulating Bmi-1 expression,” Cancer Letters, vol. 344, no. 1, pp. 40–46, 2014. View at Publisher · View at Google Scholar · View at Scopus
  28. J. Li, H. Wu, W. Li et al., “Downregulated miR-506 expression facilitates pancreatic cancer progression and chemoresistance via SPHK1/Akt/NF-κB signaling,” Oncogene, vol. 35, no. 42, pp. 5501–5514, 2016. View at Publisher · View at Google Scholar · View at Scopus
  29. J. Du, X. Zheng, S. Cai et al., “MicroRNA-506 participates in pancreatic cancer pathogenesis by targeting PIM3,” Molecular Medicine Reports, vol. 12, no. 4, pp. 5121–5126, 2015. View at Publisher · View at Google Scholar · View at Scopus
  30. S. Yu, Z. Lu, C. Liu et al., “miRNA-96 suppresses KRAS and functions as a tumor suppressor gene in pancreatic cancer,” Cancer Research, vol. 70, no. 14, pp. 6015–6025, 2010. View at Publisher · View at Google Scholar · View at Scopus
  31. H. Nagano, Y. Tomimaru, H. Eguchi et al., “MicroRNA-29a induces resistance to gemcitabine through the Wnt/β-catenin signaling pathway in pancreatic cancer cells,” International Journal of Oncology, vol. 43, no. 4, pp. 1066–1072, 2013. View at Publisher · View at Google Scholar · View at Scopus
  32. X. Lai, M. Wang, S. D. McElyea, S. Sherman, M. House, and M. Korc, “A microRNA signature in circulating exosomes is superior to exosomal glypican-1 levels for diagnosing pancreatic cancer,” Cancer Letters, vol. 393, pp. 86–93, 2017. View at Publisher · View at Google Scholar · View at Scopus
  33. M. Zoller, “Pancreatic cancer diagnosis by free and exosomal miRNA,” World Journal of Gastrointestinal Pathophysiology, vol. 4, no. 4, pp. 74–90, 2013. View at Publisher · View at Google Scholar
  34. H. Peinado, M. Alečković, S. Lavotshkin et al., “Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET,” Nature Medicine, vol. 18, no. 6, pp. 883–891, 2012. View at Publisher · View at Google Scholar · View at Scopus
  35. M. Simons and G. Raposo, “Exosomes – vesicular carriers for intercellular communication,” Current Opinion in Cell Biology, vol. 21, no. 4, pp. 575–581, 2009. View at Publisher · View at Google Scholar · View at Scopus
  36. B. Hannafon and W. Q. Ding, “Intercellular communication by exosome-derived microRNAs in cancer,” International Journal of Molecular Sciences, vol. 14, no. 7, pp. 14240–14269, 2013. View at Publisher · View at Google Scholar · View at Scopus
  37. C. Théry, L. Zitvogel, and S. Amigorena, “Exosomes: composition, biogenesis and function,” Nature Reviews Immunology, vol. 2, no. 8, pp. 569–579, 2002. View at Publisher · View at Google Scholar · View at Scopus
  38. B. T. Pan, K. Teng, C. Wu, M. Adam, and R. M. Johnstone, “Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes,” The Journal of Cell Biology, vol. 101, no. 3, pp. 942–948, 1985. View at Publisher · View at Google Scholar · View at Scopus
  39. D. D. Taylor and C. Gercel-Taylor, “MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer,” Gynecologic Oncology, vol. 110, no. 1, pp. 13–21, 2008. View at Publisher · View at Google Scholar · View at Scopus
  40. B. Madhavan, S. Yue, U. Galli et al., “Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity,” International Journal of Cancer, vol. 136, no. 11, pp. 2616–2627, 2015. View at Publisher · View at Google Scholar · View at Scopus
  41. Y. F. Xu, B. N. Hannafon, Y. D. Zhao, R. G. Postier, and W. Q. Ding, “Plasma exosome miR-196a and miR-1246 are potential indicators of localized pancreatic cancer,” Oncotarget, vol. 8, no. 44, pp. 77028–77040, 2017. View at Publisher · View at Google Scholar · View at Scopus
  42. D. Chen, X. Wu, M. Xia et al., “Upregulated exosomic miR-23b-3p plays regulatory roles in the progression of pancreatic cancer,” Oncology Reports, vol. 38, no. 4, pp. 2182–2188, 2017. View at Publisher · View at Google Scholar · View at Scopus
  43. T. Goto, M. Fujiya, H. Konishi et al., “An elevated expression of serum exosomal microRNA-191, -21, -451a of pancreatic neoplasm is considered to be efficient diagnostic marker,” BMC Cancer, vol. 18, no. 1, p. 116, 2018. View at Publisher · View at Google Scholar · View at Scopus
  44. K. Takahasi, H. Iinuma, K. Wada et al., “Usefulness of exosome-encapsulated microRNA-451a as a minimally invasive biomarker for prediction of recurrence and prognosis in pancreatic ductal adenocarcinoma,” Journal of Hepato-Biliary-Pancreatic Sciences, vol. 25, no. 2, pp. 155–161, 2018. View at Publisher · View at Google Scholar · View at Scopus
  45. S. Egawa, K. Takeda, S. Fukuyama, F. Motoi, M. Sunamura, and S. Matsuno, “Clinicopathological aspects of small pancreatic cancer,” Pancreas, vol. 28, no. 3, pp. 235–240, 2004. View at Publisher · View at Google Scholar · View at Scopus
  46. O. Ishikawa, H. Ohigashi, S. Imaoka et al., “Minute carcinoma of the pancreas measuring 1 cm or less in diameter--collective review of Japanese case reports,” Hepato-Gastroenterology, vol. 46, no. 25, pp. 8–15, 1999. View at Google Scholar
  47. J. B. Munding, A. T. Adai, A. Maghnouj et al., “Global microRNA expression profiling of microdissected tissues identifies miR-135b as a novel biomarker for pancreatic ductal adenocarcinoma,” International Journal of Cancer, vol. 131, no. 2, pp. E86–E95, 2012. View at Publisher · View at Google Scholar · View at Scopus
  48. R. Morimura, S. Komatsu, D. Ichikawa et al., “Novel diagnostic value of circulating miR-18a in plasma of patients with pancreatic cancer,” British Journal of Cancer, vol. 105, no. 11, pp. 1733–1740, 2011. View at Publisher · View at Google Scholar · View at Scopus
  49. J. Zhang, C. Y. Zhao, S. H. Zhang et al., “Upregulation of miR-194 contributes to tumor growth and progression in pancreatic ductal adenocarcinoma,” Oncology Reports, vol. 31, no. 3, pp. 1157–1164, 2014. View at Publisher · View at Google Scholar · View at Scopus
  50. C. Zhao, J. Zhang, S. Zhang et al., “Diagnostic and biological significance of microRNA-192 in pancreatic ductal adenocarcinoma,” Oncology Reports, vol. 30, no. 1, pp. 276–284, 2013. View at Publisher · View at Google Scholar · View at Scopus
  51. M. S. Lin, W. C. Chen, J. X. Huang, H. J. Gao, and H. H. Sheng, “Aberrant expression of microRNAs in serum may identify individuals with pancreatic cancer,” Journal of Clinical and Experimental Medicine, vol. 7, no. 12, pp. 5226–5234, 2014. View at Google Scholar
  52. G. A. Ganepola, J. R. Rutledge, P. Suman, A. Yiengpruksawan, and D. H. Chang, “Novel blood-based microRNA biomarker panel for early diagnosis of pancreatic cancer,” World Journal of Gastrointestinal Oncology, vol. 6, no. 1, pp. 22–33, 2014. View at Publisher · View at Google Scholar
  53. A. Li, N. Omura, S.-M. Hong et al., “Pancreatic cancers epigenetically silence SIP1 and hypomethylate and overexpress miR-200a/200b in association with elevated circulating miR-200a and miR-200b levels,” Cancer Research, vol. 70, no. 13, pp. 5226–5237, 2010. View at Publisher · View at Google Scholar · View at Scopus
  54. A. Li, J. Yu, H. Kim et al., “MicroRNA array analysis finds elevated serum mir-1290 accurately distinguishes patients with low-stage pancreatic cancer from healthy and disease controls,” Clinical Cancer Research, vol. 19, no. 13, pp. 3600–3610, 2013. View at Publisher · View at Google Scholar · View at Scopus
  55. M. Abue, M. Yokoyama, R. Shibuya et al., “Circulating miR-483-3p and miR-21 is highly expressed in plasma of pancreatic cancer,” International Journal of Oncology, vol. 46, no. 2, pp. 539–547, 2015. View at Publisher · View at Google Scholar · View at Scopus
  56. S. Zhu, H. Wu, F. Wu, D. Nie, S. Sheng, and Y. Y. Mo, “MicroRNA-21 targets tumor suppressor genes in invasion and metastasis,” Cell Research, vol. 18, no. 3, pp. 350–359, 2008. View at Publisher · View at Google Scholar · View at Scopus
  57. M. Dillhoff, J. Liu, W. Frankel, C. Croce, and M. Bloomston, “MicroRNA-21 is overexpressed in pancreatic cancer and a potential predictor of survival,” Journal of Gastrointestinal Surgery, vol. 12, no. 12, pp. 2171–2176, 2008. View at Publisher · View at Google Scholar · View at Scopus
  58. S. Ali, A. Ahmad, S. Banerjee et al., “Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF,” Cancer Research, vol. 70, no. 9, pp. 3606–3617, 2010. View at Publisher · View at Google Scholar · View at Scopus
  59. X. J. Zhang, H. Ye, C. W. Zeng, B. He, H. Zhang, and Y. Q. Chen, “Dysregulation of miR-15a and miR-214 in human pancreatic cancer,” Journal of Hematology & Oncology, vol. 3, no. 1, p. 46, 2010. View at Publisher · View at Google Scholar · View at Scopus
  60. S. Arora, S. K. Swaminathan, A. Kirtane et al., “Synthesis, characterization, and evaluation of poly (D, L-lactide-co-glycolide)-based nanoformulation of miRNA-150: potential implications for pancreatic cancer therapy,” International Journal of Nanomedicine, vol. 9, pp. 2933–2942, 2014. View at Publisher · View at Google Scholar · View at Scopus
  61. D. Pramanik, N. R. Campbell, C. Karikari et al., “Restitution of tumor suppressor microRNAs using a systemic nanovector inhibits pancreatic cancer growth in mice,” Molecular Cancer Therapeutics, vol. 10, no. 8, pp. 1470–1480, 2011. View at Publisher · View at Google Scholar · View at Scopus
  62. A. E. Frampton, J. Krell, N. B. Jamieson et al., “MicroRNAs with prognostic significance in pancreatic ductal adenocarcinoma: a meta-analysis,” European Journal of Cancer, vol. 51, no. 11, pp. 1389–1404, 2015. View at Publisher · View at Google Scholar · View at Scopus
  63. L. Liang, D. M. Wei, J. J. Li et al., “Prognostic microRNAs and their potential molecular mechanism in pancreatic cancer: a study based on the Cancer Genome Atlas and bioinformatics investigation,” Molecular Medicine Reports, vol. 17, no. 1, pp. 939–951, 2018. View at Publisher · View at Google Scholar · View at Scopus
  64. J. Namkung, W. Kwon, Y. Choi et al., “Molecular subtypes of pancreatic cancer based on miRNA expression profiles have independent prognostic value,” Journal of Gastroenterology and Hepatology, vol. 31, no. 6, pp. 1160–1167, 2016. View at Publisher · View at Google Scholar · View at Scopus