Scenario and future prospects of microRNAs in gastric cancer: A review

Document Type: Review Article

Authors

Department of Biochemistry, Govt. Medical College, Srinagar Jammu & Kashmir, India

Abstract

Carcinoma of the stomach is one of the major prevalent and principal causes of cancer-related deaths worldwide. Current advancement in technology has improved the understanding of the pathogenesis and pathology of gastric cancers (GC). But, high mortality rates, unfavorable prognosis and lack of clinical predictive biomarkers provide an impetus to investigate novel early diagnostic/prognostic markers and therapeutic targets for GC, which are sufficiently sensitive to GC. Current biomedical investigations have explored several budding GC biomarker by utilizing serum proteins, natural oncogenic genes during improvement in molecular technologies as microarray, and RNA/DNA-Seq. Recently, small non-coding microRNAs (miRNAs) are becoming vital regulators in oncogenesis pathways and can act as handy clinical biomarkers. The newly introduced class of biomarkers is rising as new molecules for cancer diagnosis and prognosis. For better understanding of the gastric carcinogenesis, miRNAs may help to elucidate the mechanisms of tumor growth and can help to discover novel untimely potent markers for early detection of GC. Here in this review, we summarize the recent research studies supporting the utility of miRNAs as novel early diagnostic/prognostic tools and therapeutic targets. Thus, here we introduce potential future treatment strategies for gastrointestinal (GI) cancers, which indicate the practicality and clinical applications of miRNAs in GC.

Keywords

Main Subjects


1.Peng Y, Croce CM. The role of MicroRNAs in human cancer. Signal Transd Targ Therapy 2016; 1: 1500.

2.Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009; 136: 215–233.

3.Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet. 2008; 9:102–114.

4.Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006; 6:857–866.

5.Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75: 843–854.

6.Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 2000; 403: 901–906.

7.Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identiļ¬cation of novel genes coding for small expressed RNAs. Science 2001; 294:853–858.

8.Lau NC, Lim LP, Weinstein EG, Bartel DP. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 2001; 294: 858–862.

9.Lee RC, Ambros V. An extensive class of small RNAs in Caenorhabditis elegans. Science 2001; 294:862–864.

10.Nassir AN, Ahmed J, Naik H, Bhat SA, Wani HA. Diagnostic utility of DAPK-gene promoter hypermethylation in gastric cancer. Int J Science Inven Today. 2017; 6(5): 646-658.

11.Showkat AB, Manzoor RM, Sabhiya M, Rehman MU, Kuchy S, Sheikh SB, Husain I, Das BC. Environmental Factors in Etiology of Gastric Cancer. Adv Biochem. 2015; 3(5): 51-56.

12.Showkat AB, Mir MUR, Majid S, Tehseen H, Rehman MU, Kuchy S. Diagnostic utility of glycosyltransferase mRNA expression in gastric cancer. Hematol Oncol Stem Cell Ther. 2018: 1658-3876.

13.Smith HC. The role of microRNAs in gastric cancer. Am J Digest Dis 2016;3(3):29-37.

14.Tsujiura M, Ichikawa D, Komatsu S, Shiozaki A, Takeshita H, Kosuga T, et al. Circulating microRNAs in plasma of patients with gastric cancers. Br. J. Cancer 2010; 102:1174–1179.

15.Gorur A, Fidanci SB,  Unal ND, Ayaz L, Hatice SA, Yaroglu Y et al. Determination of plasma microRNA for early detection of gastric cancer. Mol Biol Rep 2013; 40(3): 2091–2096.

16.Abbas M, Habib M, Naveed M, Karthik K, Dhama K, Shi M, Dingding C. The relevance of gastric cancer biomarkers in prognosis and pre- and post- chemotherapy in clinical practice. Biomed Pharmacotherap. 2017:95:1082-1090.

17.Hundahl SA, Stemmermann, GN, Oishi A. Racial factors cannot explain superior Japanese outcomes in stomach cancer. Arch. Surg. 1996; 131: 170–175.

18.Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281-297.

19.Rossbach M. Small non-coding RNAs as novel therapeutics. Curr Mol Med 2010; 10: 361-368.

20.Nelson KM, Weiss GJ. MicroRNAs and cancer: past, present, and potential future. Mol Cancer Ther 2008; 7: 3655-3660.

21.MacFarlane L, Murphy PR. MicroRNA: biogenesis, function, and role in cancer. Curr Genomics 2010; 11: 537-561.

22.Starega-Roslan J, Koscianska E, Kozlowski P, Krzyzosiak WJ. The role of the precursor structure in the biogenesis of microRNA. Cell Mol Life Sci 2011; 68: 2859.

23.Selbach M, Schwannhausser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N. Widespread changes in protein synthesis induced by microRNAs. Nature 2008; 255: 58-53.

24.Baek D, Villen J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature 2008; 455: 64-71.

25.Davis ME, Zuckerman JE, Choi CHJ, Seligson D, Tolcher A, Alabi CA, Yen Y, Heidel JD, Ribas A. Evidence of RNAi in hmans from systematically administered siRNA via targeted nanoparticles. Nature 2010; 464: 1067-1070.

26.Ambs S, Prueitt RL, Yi M, Hudson RS, Howe TM, Petrocca F, Wallace TA, Liu C, Volinia S, Calin GA, Yfantis HG, Stephen RM, Croce CM. Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res 2008; 68: 6162.

27.Lee YS, Dutta A. MicroRNAs in cancer. Annu Rev Pathol 2009; 4: 199-227.

28.Vasudevan S. Posttranscriptional upregulation by microRNAs. Wiley Interdiscip Rev RNA 2012; 3: 311-330

29.Orang AV, Safaralizadeh R, Kazemzadeh-Bavili M. Mechanisms of miRNA-mediated gene regulation from common downregulation to mRNA-specific upregulation. Int J Genomics 2014; 2014: 1-15.

30.Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: microRNAs can upregulate translation. Science 2007; 318: 1931-1934.

31.Zhang W, Dahlberg JE, and  Tam W. MicroRNAs in Tumorigenesis. The American Journal of Pathology, 2007, 171:728–738.

32.Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM: Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 2004; 101:2999–3004.

33.Zhang L, Huang J, Yang N, Greshock J, Megraw MS, Giannakakis A, et al.  MicroRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci USA 2006; 103:9136–9141

34.O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT: c-Mycregulated microRNAs modulate E2F1 expression. Nature 2005; 435:839–843

35.Showkat AB, Sabhiya M, Muneeb UR. Diagnostic Utility of miRNAs in Cancer. Multidisciplinary Cancer Investigation,  2018; 2:3 5-15.

36.Zhu S, Wu H, Wu F, Nie D, Sheng S, Mo Y. MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res 2008; 18: 350-359.

37.Folini M, Gandellini P, Longoni N, Profumo V, Callari M, Pennati M, Colecchia M, Supino R, Veneroni S, Salvioni R, Valdagni R, Daidone MG, Zaffaroni N. MiR-21: an oncomirs on strike in prostate cancer. Mol Cancer 2010; 9: 12.

38.Deng S, Calin GA, Croce CM, Coukos G, Zhang L. Mechanisms of microRNA deregulation in human cancer. Cell Cycle 2008; 7: 2643-2646.

39.Linsley PS, Schelter J, Burchard J, Kibukawa M, Martin MM, Bartz SR, Johnson JM, Cummins JM, Raymond CK, Dai H, Chau N, Cleary M, Jackson AL, Carleton M, Lim L. Transcripts targeted by the microRNA-16 family cooperatively regulate cell cycle progression. Mol Cell Biol, 2007; 27: 2240-2252.

40.Jansson MD, Lund AH. MicroRNA and cancer. Mol Oncol 2012; 6: 590-610.

41.Nissar AN, Showkat AB, Sabhiya M, Hilal AW, Roohi A, Rafiqa E, Tehseen H, Akbar M. Scenario of epigenetic alterations and gastric cancer-a review. International Journal of Recent Scientific Research, 2018, 9:5; 26679-26687.

42.Matsubara H, Takeuchi T, Nishikawa E, Yanagisawa K, Hayashita Y, Ebi H, Yamada H, Suzuki M, Nagino M, Nimura Y,Osada H, Takahashi T. Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92. Oncogene 2007; 26: 6099-6105.

43.Cahill S, Smyth P, Finn SP, Denning K, Flavin R, O’Regan EM, Li J, Potratz A, Guenther SM, Henfrey R, O’Leary JJ, Sheils O. Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model. Mol Cancer 2006; 5: 70.

44.Di Mario F, Cavallaro LG. Non-invasive tests in gastric diseases. Dig Liver Dis 2008; 40: 523-530.

45.Han-Shao Liu, Hua-Sheng Xiao. MicroRNAs as potential biomarkers for gastric cancer. World J Gastroenterol 2014 ; 20(34): 12007-12017

46.Marco Tomasetti, Wan Lee, Lory Santarelli, Jiri Neuzil. "Exosome-derived microRNAs in cancer metabolism: possible implications in cancer diagnostics and therapy", Experimental & Molecular Medicine, 2017.

47.Hua-Hsi Wu, Wen-chang Lin, Kuo-Wang Tsai. Advances in molecular biomarkers for gastric cancer: miRNAs as emerging novel cancer markers.  Expert Reviews in Molecular Medicine, 2014; 16-e1.

48.Poy MN, Eliasson L,  Krutzfeldt  J,  Kuwajima  S, Ma  X,  Macdonald PE.  et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature 2004; 432: 226–230.

49.Poliseno L, Tuccoli  A,  Mariani  L,  Evangelista M,  Citti  L. Woods, K.; et al. MicroRNAs modulate the angiogenic properties of HUVECs. Blood 2006; 108: 3068–3071.

50.Calin GA,  Sevignani  C,  Dumitru  CD,  Hyslop  T,  Noch  E,  Yendamuri S. et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc. Natl. Acad. Sci. USA 2004; 101: 2999–3004.

51.Link A, Kupcinskas J, Wex T, Malfertheiner P. Macro-Role of microRNA in gastric cancer. Dig. Dis. 2012; 30: 255–267.

52.Cho WJ. Shin JM, Kim JS, Lee MR, Hong KS, Lee JH  et al. MiR-372 regulates cell cycle and apoptosis of AGS human gastric cancer cell line through direct regulation of LATS2. Mol. Cells 2009;28: 521–527.

53.Zhang X, Zhu W, Zhang J,  Huo S, Zhou L, Gu Z. et al.  MicroRNA-650 targets ING4 to promote gastric cancer tumorigenicity. Biochem. Biophys. Res. Commun. 2010; 395: 275–280.

54.Pan J, Hu H, Zhou Z, Sun L, Peng L, Yu L. et al. Tumor-suppressive mir-663 gene induces mitotic catastrophe growth arrest in human gastric cancer cells. Oncol. Rep. 2010; 24: 105–112.

55.Otsubo T, Akiyama Y, Hashimoto Y, Shimada S, Goto K, Yuasa Y. MicroRNA-126 inhibits SOX2 expression and contributes to gastric carcinogenesis. PLoS One 2011; 6: e16617.

56.Wan HY, Guo LM, Liu T, Liu M, Li X. Tang H. Regulation of the transcription factor NF-κB1 by microRNA-9 in human gastric adenocarcinoma. Mol. Cancer 2010; 9: 16.

57.Song YX, Yue ZY, Wang ZN,  Xu YY Luo, Y,  Xu, HM. MicroRNA-148b is frequently down-regulated in gastric cancer and acts as a tumor suppressor by inhibiting cell proliferation. Mol. Cancer 2011; 10: 1.

58.Yang Q, Jie Z,  Cao H,  Greenlee AR, Yang C, Zou F, Jiang Y. Low-level expression of let-7a in gastric cancer and its involvement in tumorigenesis by targeting RAB40C. Carcinogenesis 2011; 32: 713–722.

59.Bandres E, Bitarte N, Arias F, Agorreta J, Fortes P, Agirre X, Zarate R, Diaz-Gonzalez JA, Ramirez N, Sola JJ, Jimenez P, Rodriguez J, Garcia-Foncillas J. microRNA-451 regulates macrophage migration inhibitory factor production and proliferation of gastrointestinal cancer cells. Clin Cancer Res 2009;15:2281-90.

60.Du, Y.; Xu, Y.; Ding, L.; Yao, H.; Yu, H.; Zhou, T.; Si, J. Down-regulation of miR-141 in gastric cancer and its involvement in cell growth. J. Gastroenterol. 2009, 44, 556–561.

61.Lang, N.; Liu, M.; Tang, Q.L.; Chen, X.; Liu, Z.; Bi, F. Effects of microRNA-29 family members on proliferation and invasion of gastric cancer cell lines. Chin. J. Cancer 2010, 29, 603–610.

62.Wang, B.; Zhang, Q. The expression and clinical significance of circulating microRNA-21 in serum of five solid tumors. J. Cancer Res. Clin. Oncol. 2012, doi:10.1007/s00432-012-1244-9.

63.Li X, Zhang Y, Zhang Y, Ding J, Wu K, Fan D. Survival prediction of gastric cancer by a seven microRNA signature. Gut 2010;59:579-85.

64.Chen L, Jiang M, Yuan W, Tang H. Prognostic value of miR-93 overexpression in resectable gastric adenocarcinomas. Acta Gastroenterol Belg 2012;75:22-7.

65.Tie J, Pan Y, Zhao L, Wu K, Liu J, Sun S, Guo X, Wang B, Gang Y, Zhang Y, Li Q, Qiao T, Zhao Q, Nie Y, Fan D. MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor. PLoS Genet 2010;6:e1000879.

66.Ueda T, Volinia S, Okumura H, Shimizu M, Taccioli C, Rossi S, Alder H, Liu CG, Oue N, Yasui W, Yoshida K, Sasaki H, Nomura S, Seto Y, Kaminishi M, Calin GA, Croce CM. Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis. Lancet Oncol 2010;11:136-46.

67.Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Research, 2008; 18: 997-1006.

68.Gilad S, Meiri E, Yogev Y, Benjamin S, Lebanony D, Yerushalmi  N. Serum microRNAs are promising novel biomarkers. PLoS One 2008; 3: e3148.

69.Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman, SK. Pogosova-Agadjanyan EL. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl. Acad. Sci. USA 2008; 105: 10513–10518.

70.Cai H, Yuan Y, Hao YF, Guo TK, Wei X, Zhang YM. Plasma microRNAs serve as novel potential biomarkers for early detection of gastric cancer. Med Oncol 2013; 30: 452.

71.Gorur A, Balci Fidanci S, Dogruer Unal N, Ayaz L, Akbayir S, Yildirim Yaroglu H, Dirlik M, Serin MS, Tamer L. Determination of plasma microRNA for early detection of gastric cancer. Mol Biol Rep 2013; 40: 2091-2096.

72.Chim SS, Shing TK, Hung EC, Leung TY, Lau TK, Chiu RW. Detection and characterization of placental microRNAs in maternal plasma. Clinical Chemistry 2008; 54: 482-490

73.Lodes MJ, Caraballo M, Suciu D, Munro S,  Kumar A. Anderson  B. Detection of cancer with serum miRNAs on an oligonucleotide microarray. PLoS One 2009; 4: e6229.

74.Komatsu S, Ichikawa D, Tsujiura M, Konishi H, Takeshita H, Nagata H, et al.. Prognostic impact of circulating miR-21 in the plasma of patients with gastric carcinoma. Anticancer Res 2013; 33: 271-276.

75.Liu K, Li G, Fan C, Diao Y, Wu B, Li J. Increased expression of microRNA-221 in gastric cancer and its clinical significance. J. Int. Med. Res. 2012; 40: 467–474.

76.Wang WN, Chen Y, Zhang YD, Hu TH. The regulatory mechanism of CCR7 gene expression and its involvement in the metastasis and progression of gastric cancer. Tumour Biol 2013; 34: 1865-1871.

77.Esau CC. Inhibition of microRNA with antisense oligonucleotides. Methods 2008; 44: 55-60.

78.Kim SY, Jeon TY, Choi CI, Kim DH, Kim DH, Kim GH, Ryu DY, Lee BE, Kim HH. Validation of circulating miRNA biomarkers for predicting lymph node metastasis in gastric cancer. J Mol Diagn 2013; 15: 661-669.

79.Konishi H, Ichikawa D, Komatsu S, Shiozaki A, Tsujiura M, Takeshita H. Detection of gastric cancerassociated microRNAs on microRNA microarray comparing pre- and post-operative plasma. British Journal of Cancer 2012; 106:740-747

80.Li C, Li JF, Cai Q, Qiu QQ, Yan M, Liu BY, Zhu ZG. MiRNA- 199a-3p: A potential circulating diagnostic biomarker for early gastric cancer. J Surg Oncol 2013a; 108: 89-92.

81.Li C, Li JF, Cai Q, Qiu QQ, Yan M, Liu BY, Zhu ZG. miRNA- 199a-3p in plasma as a potential diagnostic biomarker for gastric cancer. Ann Surg Oncol 2013b; 20(3): 397-405.

82.Li BS. Plasma microRNAs, miR-223, miR-21 and miR-218, as novel potential biomarkers for gastric cancer detection. PLoS ONE 2012; 7: e41629

83.Liu R, Zhang C, Hu Z, Li G, Wang C, Yang C et al. A five-microRNA signature identified from genome-wide serum microRNA expression profiling serves as a fingerprint for gastric cancer diagnosis. Eur. J. Cancer 2011;47: 784–791.

84.Song MY, Pan KF, Su HJ, Zhang L, Ma JL, Li JY. Identification of serum microRNAs as novel non-invasive biomarkers for early detection of gastric cancer., PLoS ONE 2012;7: e33608

85.Cui L, Zhang X, Ye G, Zheng T, Song H, Deng H. Gastric juice microRNAs as potential biomarkers for the screening of gastric cancer. Cancer. 2013; 119: 1618-1626.

86.Zhang X, Cui L, Ye G, Zheng T, Song H,  Xia  T. Gastric juice microRNA-421 is a new biomarker for screening gastric cancer Gastric juice microRNA-421 is a new biomarker for screening gastric cancer. Tumour Biology. 2012;  33:  2349-2355.

87.Cho WC. Great potential of miRNAs as predictive and prognostic markers for cancer. Expert Rev. Mol. Diagn. 2012a; 12: 315–318.

88.Cho WC. MicroRNAs as therapeutic targets and their potential applications in cancer therapy. Expert Opin. Ther. Targets 2012b; 16: 747–759.

89.Navari M, Etebari M, Ibrahimi M, Leoncini L, Piccaluga PP. Pathobiologic Roles of Epstein–Barr Virus-Encoded MicroRNAs in Human Lymphomas. International Journal of Molecular Sciences, 2018 ; 19(4): 11682018.

90.Guo J, Miao Y, Xiao B,  Huan R,  Jiang Z,  Meng  D. et al. Differential expression of microRNA species in human gastric cancer versus non-tumorous tissues. J. Gastroenterol. Hepatol 2009; 24: 652–657.

91.Yao Y, Suo AL, Li ZF, Liu LY, Tian Tet al.  MicroRNA profiling of human gastric cancer. Mol. Med. Report 2009; 2: 963–970.

92.Motoyama K, Inoue H, Mimori K, Tanaka F, Kojima  K, Uetake H, Sugihara K, Mori M. Clinicopathological and prognostic significance of PDCD4 and microRNA-21 in human gastric cancer. Int. J. Oncol. 2010; 36: 1089–1095.

93.Nishida N. Mimori K. Fabbri M, Yokobor T, Sudo T, Tanaka F.MicroRNA-125a-5p is an independent prognostic factor in gastric cancer and inhibits the proliferation of human gastric cancer cells in combination with trastuzumab. Clin. Cancer Res. 2011; 17: 2725–2733.

94.Zheng B, Liang L, Huang S, Zha R, Liu L,  Jia D et al. MicroRNA-409 suppresses tumor cell invasion and metastasis by directly targeting radixin in gastric cancers. Oncogene. 2012; 18(31):4509-4516

95.Inoue T, Iinuma H, Ogawa E, Inaba T, Fukushima R. Clinicopathological and prognostic significance of microRNA-107 and its relationship to DICER1 mRNA expression in gastric cancer. Oncol. Rep. 2012;27: 1759–1764.

96.Li X, Zhang Y, Zhang Y, Ding J, Wu K, Fan D. Survival prediction of gastric cancer by a seven microRNA signature. Gut 2010;59:579-85.

97.Tsai KW, Liao YL, Wu CW, Hu LY, Li SC, Chan WC. et al. Aberrant expression of miR-196a in gastric cancers and correlation with recurrence. Genes Chromosomes Cancer 2012; 51:  394–401.

98.Yu DC, Li QG, Ding XW, Ding YT. Circulating microRNAs: Potential biomarkers for cancer. Int. J. Mol. Sci. 2011; 12: 2055–2063.

99.Kosaka N, Iguchi H, Ochiya T. Circulating microRNA in body fluid: A new potential biomarker for cancer diagnosis and prognosis. Cancer Sci. 2010; 101: 2087–2092.

100.Chen C, Ridzon DA,  Broomer  AJ,  Zhou Z,  Lee DH,  Nguyen JT,  et al. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 2005; 33: e179.

101.Kozomara A, Griffiths-Jones S. MiRBase: Integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 2011; 39: 152–157.

102.Aqeilan RI, Calin GA, Croce CM. MiR-15a and miR-16-1 in cancer: discovery, function, and future prospectives. Cell Death Differ 2010; 17: 215-220.

103.Horikawa Y, Wood CG, Yang G, Zhao H, Ye Y, Gu J, Lin J, Habuchi T, Wu W. Single nucleotide polymorphisms of microRNA machinery genes modify risk of renal cell carcinoma. Clin Cancer Res 2008; 14: 7956.

104.Naidu S, Magee P, Garofalo M. MiRNA-based therapeutic intervention of cancer. J Hematol Oncol 2015; 8: 68.

105.Bader AG, Brown D, Winkler M. The promise of microRNA replacement therapy. Cancer Res 2010; 70: 7027-7030.

106.Chen Y, Gao D, Huang L. In vivo delivery of miRNAs for cancer therapy: challenges and strategies. Adv Drug Deliver Rev 2015; 81: 128-141.

107.Stylianopoulos T, Jain RK. Combining two strategies to improve perfusion and drug delivery in solid tumors. Proc Natl Acad Sci U S A 2012; 110: 18632-18637.

108.Raemdonck K, Vandenbroucke RE, Demeester J, Sanders NN, Smedt SC. Maintaining the silence: reflections on long-term RNAi. Drug Discov Today 2008; 31: 917-31.

109.Van DS, Abreu-Goodger C, Enright AJ. Detecting microRNA binding and siRNA off-target effects from expression data. Nat Methods 2008; 5: 1023-1025.

110.Treece AL, Duncan DL, Tang W, Elmore S, Morgan DR, Dominguez RL, et al. Gastric adenocarcinoma microRNA profiles in fixed tissue and in plasma reveal cancer-associated and Epstein-Barr virus-related expression patterns. Laboratory Investigation 2016; 96: 661–671.

111.Lin Zhang, Yuchen Zhang, Sunny H. Wong, Priscilla T. Y. Law, Shan Zhao, Jun Yu, Matthew T. V. Chan & William K. K. Wu. Common Deregulation of Seven Biological Processes by MicroRNAs in Gastrointestinal Cancers. Scientific Reports 8: 3287, 2018.

112.Petrocca F, Vecchione A, Croce CM. Emerging role of miR-106b-25/miR-17-92 clusters in control of transforming growth factor β signaling. Cancer Res 2008; 68: 8191.

113.Hamano R, Miyata H, Yamasaki M., et al. Overexpression of miR-200c induces chemoresistance in esophageal cancers mediated through activation of the Akt signaling pathway. Clin Cancer Res 2011;17:3029-38.

114.Yi B, Liu D, He M, Li Q, Liu T, Shao J. Role of the ROS/AMPK signaling pathway in tetramethylpyrazine-induced apoptosis in gastric cancer cells. Oncol Lett. 2013; 6: 583.