Downregulation of the let‑7 family of microRNAs may promote insulin receptor/insulin‑like growth factor signalling pathways in pancreatic ductal adenocarcinoma

Nweke,Ekene   Emmanuel; Brand,Martin

doi:10.3892/ol.2020.11854

Downregulation of the let‑7 family of microRNAs may promote insulin receptor/insulin‑like growth factor signalling pathways in pancreatic ductal adenocarcinoma

Authors:
- Ekene Emmanuel Nweke
- Martin Brand
View Affiliations

Affiliations: Department of Surgery, Faculty of Health Sciences, University of The Witwatersrand, Johannesburg 2193, South Africa, School of Physiology, Faculty of Health Sciences, University of The Witwatersrand, Johannesburg 2193, South Africa
Published online on: July 10, 2020 https://doi.org/10.3892/ol.2020.11854
Pages: 2613-2620
Copyright: © Nweke et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer type characterized by dysregulated cell signalling pathways and resistance to treatment. The insulin‑like growth factor (IGF) signalling pathway has been identified to have a role in tumour progression and therapy resistance. However, its regulatory roles in PDAC have remained to be fully elucidated. In the present study, dysregulated microRNAs (miRNAs) in PDAC were explored with a focus on those that may be involved in regulating the insulin/IGF signalling pathway. A total of 208 patients were recruited, comprising 112 patients with PDAC, 50 patients with chronic pancreatitis (CP) and 46 subjects as a control group (CG). miRNA‑specific quantitative PCR assays were used to measure 300 candidate miRNAs. The Student's t‑test was applied to compare miRNA regulation between cancer patients and controls with a false discovery rate correction using Bonferroni‑type comparison procedures. The DIANA‑mirPath v.3 tool and HMDD v3.0 were used to identify miRNA‑mRNA interactions within specific pathways. In patients with PDAC, 42 miRNAs were significantly upregulated and 42 were downregulated compared to the CG (P<0.01). In the PDAC vs. CP analysis, 16 significantly (P<0.01) upregulated and 16 downregulated miRNAs were identified. Of note, members of the let‑7 family of miRNAs were downregulated and were indicated to target several components of the insulin receptor (INSR)/IGF pathway, including receptors and binding proteins, for upregulation and thus, may enable the activation of the pathway. Downregulation of the let‑7 family may help promote the INSR/IGF pathway in PDAC. It may thus be an effective target for the development of INSR/IGF pathway‑specific treatment strategies.

View Figures

View References

1	Rawla P, Sunkara T and Gaduputi V: Epidemiology of pancreatic cancer: Global trends, etiology and risk factors. World J Oncol. 10:10–27. 2019. View Article : Google Scholar : PubMed/NCBI
2	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
3	Ferrone CR, Brennan MF, Gonen M, Coit DG, Fong Y, Chung S, Tang L, Klimstra D and Allen PJ: Pancreatic adenocarcinoma: The actual 5-year survivors. J Gastrointest Surg. 12:701–706. 2008. View Article : Google Scholar : PubMed/NCBI
4	Trajkovic-Arsic M, Kalideris E and Siveke JT: The role of insulin and IGF system in pancreatic cancer. J Mol Endocrinol. 50:R67–R74. 2013. View Article : Google Scholar : PubMed/NCBI
5	Valsecchi ME, McDonald M, Brody JR, Hyslop T, Freydin B, Yeo CJ, Solomides C, Peiper SC and Witkiewicz AK: Epidermal growth factor receptor and insulinlike growth factor 1 receptor expression predict poor survival in pancreatic ductal adenocarcinoma. Cancer. 118:3484–3493. 2012. View Article : Google Scholar : PubMed/NCBI
6	Nandy D and Mukhopadhyay D: Growth factor mediated signaling in pancreatic pathogenesis. Cancers (Basel). 3:841–871. 2011. View Article : Google Scholar : PubMed/NCBI
7	Faller BA and Burtness B: Treatment of pancreatic cancer with epidermal growth factor receptor-targeted therapy. Biologics. 3:419–428. 2009.PubMed/NCBI
8	Zielinski R, Przytycki PF, Zheng J, Zhang D, Przytycka TM and Capala J: The crosstalk between EGF, IGF, and Insulin cell signaling pathways-computational and experimental analysis. BMC Syst Biol. 3:882009. View Article : Google Scholar : PubMed/NCBI
9	Bergmann U: Insulin-like growth factor I overexpression in human pancreatic cancer: Evidence for autocrine and paracrine roles. Cancer Res. 55:2007–2011. 1995.PubMed/NCBI
10	Chakravarti A, Loeffler JS and Dyson NJ: Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res. 62:200–207. 2002.PubMed/NCBI
11	LeRoith D and Roberts Jr CT: The insulin-like growth factor system and cancer. Cancer Lett. 195:127–137. 2003. View Article : Google Scholar : PubMed/NCBI
12	Mutgan AC, Besikcioglu HE, Wang S, Friess H, Ceyhan GO and Demir IE: Insulin/IGF-driven cancer cell-stroma crosstalk as a novel therapeutic target in pancreatic cancer. Mol Cancer. 17:662018. View Article : Google Scholar : PubMed/NCBI
13	Singh P, Alex JM and Bast F: Insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R) signaling systems: Novel treatment strategies for cancer. Med Oncol. 31:8052014. View Article : Google Scholar : PubMed/NCBI
14	Liu W, Bloom DA, Cance WG, Kurenova EV, Golubovskaya VM and Hochwald SN: FAK and IGF-IR interact to provide survival signals in human pancreatic adenocarcinoma cells. Carcinogenesis. 29:1096–1107. 2008. View Article : Google Scholar : PubMed/NCBI
15	Ma J, Sawai H, Matsuo Y, Ochi N, Yasuda A, Takahashi H, Wakasugi T, Funahashi H, Sato M and Takeyama H: IGF-1 mediates PTEN suppression and enhances cell invasion and proliferation via activation of the IGF-1/PI3K/Akt signaling pathway in pancreatic cancer cells. J Surg Res. 160:90–101. 2010. View Article : Google Scholar : PubMed/NCBI
16	Neid M, Datta K, Stephan S, Khanna I, Pal S, Shaw L, White M and Mukhopadhyay D: Role of insulin receptor substrates and protein kinase C-zeta in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells. J Biol Chem. 279:3941–3948. 2004. View Article : Google Scholar : PubMed/NCBI
17	Nweke E, Ntwasa M, Brand M, Devar J, Smith M and Candy G: Increased expression of plakoglobin is associated with upregulated MAPK and PI3K/AKT signalling pathways in early resectable pancreatic ductal adenocarcinoma. Oncol Lett. 19:4133–4141. 2020.PubMed/NCBI
18	Khan MA, Zubair H, Srivastava SK, Singh S and Singh AP: Insights into the role of microRNAs in pancreatic cancer pathogenesis: Potential for diagnosis, prognosis, and therapy. Adv Exp Med Biol. 889:71–87. 2015. View Article : Google Scholar : PubMed/NCBI
19	Mattick JS and Gagen MJ: The evolution of controlled multitasked gene networks: The role of introns and other noncoding RNAs in the development of complex organisms. Mol Biol Evol. 18:1611–1630. 2001. View Article : Google Scholar : PubMed/NCBI
20	Gong L, Wang C, Gao Y and Wang J: Decreased expression of microRNA-148a predicts poor prognosis in ovarian cancer and associates with tumor growth and metastasis. Biomed Pharmacother. 83:58–63. 2016. View Article : Google Scholar : PubMed/NCBI
21	Ono S, Lam S, Nagahara M and Hoon DS: Circulating microRNA biomarkers as liquid biopsy for cancer patients: Pros and cons of current assays. J Clin Med. 4:1890–1907. 2015. View Article : Google Scholar : PubMed/NCBI
22	Vafaee F, Diakos C, Kirschner MB, Reid G, Michael MZ, Horvath LG, Alinejad-Rokny H, Cheng ZJ, Kuncic Z and Clarke S: A data-driven, knowledge-based approach to biomarker discovery: Application to circulating microRNA markers of colorectal cancer prognosis. NPJ Syst Biol Appl. 4:202018. View Article : Google Scholar : PubMed/NCBI
23	Bratulic S, Gatto F and Nielsen J: The translational status of cancer liquid biopsies. Regen Eng Transl Med. Nov 25–2019. View Article : Google Scholar
24	Lawrie CH, Gal S, Dunlop HM, Pushkaran B, Liggins AP, Pulford K, Banham AH, Pezzella F, Boultwood J, Wainscoat JS, et al: Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol. 141:672–675. 2008. View Article : Google Scholar : PubMed/NCBI
25	Chun YS, Pawlik TM and Vauthey JN: 8th Edition of the AJCC Cancer Staging Manual: Pancreas and Hepatobiliary cancers. Ann Surg Oncol. 25:845–847. 2018. View Article : Google Scholar : PubMed/NCBI
26	Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N and Conde JG: Research electronic data capture (REDCap)-A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 42:377–381. 2009. View Article : Google Scholar : PubMed/NCBI
27	Conwell DL, Lee LS, Yadav D, Longnecker DS, Miller FH, Mortele KJ, Levy MJ, Kwon R, Lieb JG, Stevens T, et al: American pancreatic association practice guidelines in chronic pancreatitis: Evidence-based report on diagnostic guidelines. Pancreas. 43:1143–1162. 2014. View Article : Google Scholar : PubMed/NCBI
28	Löhr JM, Dominguez-Munoz E, Rosendahl J, Besselink M, Mayerle J, Lerch MM, Haas S, Akisik F, Kartalis N, Iglesias-Garcia J, et al: United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU). United European Gastroenterol J. 5:153–199. 2017. View Article : Google Scholar : PubMed/NCBI
29	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
30	Lanoix D, Lacasse AA, St-Pierre J, Taylor SC, Ethier-Chiasson M, Lafond J and Vaillancourt C: Quantitative PCR Pitfalls: The case of the human placenta. Mol Biotechnol. 52:234–243. 2012. View Article : Google Scholar : PubMed/NCBI
31	St-Pierre J, Grégoire JC and Vaillancourt C: A simple method to assess group difference in RT-qPCR reference gene selection using GeNorm: The case of the placental sex. Sci Rep. 7:169232017. View Article : Google Scholar : PubMed/NCBI
32	Chen SY, Feng Z and Yi X: A general introduction to adjustment for multiple comparisons. J Thorac Dis. 9:1725–1729. 2017. View Article : Google Scholar : PubMed/NCBI
33	Reneker J and Shyu CR: Applying sequential forward floating selection to protein structure prediction with a study of HIV-1 RP. AMIA Annu Symp Proc. 2006:10722006.
34	Vlachos IS, Zagganas K, Paraskevopoulou MD, Georgakilas G, Karagkouni D, Vergoulis T, Dalamagas T and Hatzigeorgiou AG: DIANA-miRPath v3.0: Deciphering microRNA function with experimental support. Nucleic Acids Res. 43:W460–W466. 2015. View Article : Google Scholar : PubMed/NCBI
35	Karagkouni D, Paraskevopoulou MD, Chatzopoulos S, Vlachos IS, Tastsoglou S, Kanellos I, Papadimitriou D, Kavakiotis I, Maniou S, Skoufos G, et al: DIANA-TarBase v8: A decade-long collection of experimentally supported miRNA-gene interactions. Nucleic Acids Res. 46:D239–D245. 2018. View Article : Google Scholar : PubMed/NCBI
36	Kanehisa M and Goto S: KEGG: Kyoto Encyclopedia of genes and genomes. Nucleic Acids Res. 28:27–30. 2000. View Article : Google Scholar : PubMed/NCBI
37	Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, Franz M, Grouios C, Kazi F, Lopes CT, et al: The GeneMANIA prediction server: Biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 38:W214–W220. 2010. View Article : Google Scholar : PubMed/NCBI
38	Huang Z, Shi J, Gao Y, Cui C, Zhang S, Li J, Zhou Y and Cui Q: HMDD v3.0: A database for experimentally supported human microRNA-disease associations. Nucleic Acids Res. 47:D1013–D1017. 2019. View Article : Google Scholar : PubMed/NCBI
39	Kirkegård J, Mortensen FV and Cronin-Fenton D: Chronic pancreatitis and pancreatic cancer Risk: A systematic review and meta-analysis. Am J Gastroenterol. 112:1366–1372. 2017. View Article : Google Scholar : PubMed/NCBI
40	Li Y, VandenBoom TG, Kong D, Wang Z, Ali S, Philip PA and Sarkar FH: Up-regulation 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 Res. 69:6704–6712. 2009. View Article : Google Scholar : PubMed/NCBI
41	Boyerinas B, Park SM, Hau A, Murmann AE and Peter ME: The role of let-7 in cell differentiation and cancer. Endocr Relat Cancer. 17:F19–F36. 2010. View Article : Google Scholar : PubMed/NCBI
42	Encarnación J, Ortiz C, Vergne R, Vargas W, Coppola D and Matta JL: High DRC levels are associated with Let-7b overexpression in women with breast cancer. Int J Mol Sci. 17:8652016. View Article : Google Scholar
43	Perkhofer L, Illing A, Gout J, Frappart PO and Kleger A: Precision medicine meets the DNA damage response in pancreatic cancer. Oncoscience. 5:6–8. 2018. View Article : Google Scholar : PubMed/NCBI
44	McWilliams RR, Bamlet WR, Cunningham JM, Goode EL, de Andrade M, Boardman LA and Petersen GM: Polymorphisms in DNA repair genes, smoking, and pancreatic adenocarcinoma risk. Cancer Res. 68:4928–4935. 2008. View Article : Google Scholar : PubMed/NCBI
45	Torrisani J, Bournet B, du Rieu MC, Bouisson M, Souque A, Escourrou J, Buscail L and Cordelier P: let-7 MicroRNA transfer in pancreatic cancer-derived cells inhibits in vitro cell proliferation but fails to alter tumor progression. Hum Gene Ther. 20:831–844. 2009. View Article : Google Scholar : PubMed/NCBI
46	Bao B, Ali S, Banerjee S, Wang Z, Logna F, Azmi AS, Kong D, Ahmad A, Li Y, Padhye S and Sarkar FH: Curcumin analogue CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression. Cancer Res. 72:335–345. 2012. View Article : Google Scholar : PubMed/NCBI
47	Bracci PM: Obesity and pancreatic cancer: Overview of epidemiologic evidence and biologic mechanisms. Mol Carcinog. 51:53–63. 2012. View Article : Google Scholar : PubMed/NCBI
48	Bowers LW, Rossi EL, O'Flanagan CH, deGraffenried LA and Hursting SD: The role of the Insulin/IGF system in cancer: Lessons learned from clinical trials and the energy balance-cancer link. Front Endocrinol (Lausanne). 6:772015. View Article : Google Scholar : PubMed/NCBI
49	Zhu H, Shyh-Chang N, Segrè AV, Shinoda G, Shah SP, Einhorn WS, Takeuchi A, Engreitz JM, Hagan JP, Kharas MG, et al: The Lin28/let-7 axis regulates glucose metabolism. Cell. 147:81–94. 2011. View Article : Google Scholar : PubMed/NCBI
50	Bailyes EM, Navé BT, Soos MA, Orr SR, Hayward AC and Siddle K: Insulin receptor/IGF-I receptor hybrids are widely distributed in mammalian tissues: Quantification of individual receptor species by selective immunoprecipitation and immunoblotting. Biochem J. 327:209–215. 1997. View Article : Google Scholar : PubMed/NCBI
51	Pollak M: Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 8:915–928. 2008. View Article : Google Scholar : PubMed/NCBI
52	Ohmura E, Okada M, Onoda N, Kamiya Y, Murakami H, Tsushima T and Shizume K: Insulin-like growth factor I and transforming growth factor alpha as autocrine growth factors in human pancreatic cancer cell growth. Cancer Res. 50:103–107. 1990.PubMed/NCBI
53	Ulanet DB, Ludwig DL, Kahn CR and Hanahan D: Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy. Proc Natl Acad Sci USA. 107:10791–10798. 2010. View Article : Google Scholar : PubMed/NCBI
54	Brahmkhatri VP, Prasanna C and Atreya HS: Insulin-Like growth factor system in cancer: Novel targeted therapies. Biomed Res Int. 2015:5380192015. View Article : Google Scholar : PubMed/NCBI
55	Eich ML, Tregnago AC, Faraj SF, Palsgrove DN, Fujita K, Bezerra SM, Munari E, Sharma R, Chaux A and Netto GJ: Insulin-like growth factor-1 receptor expression in upper tract urothelial carcinoma. Virchows Arch. 474:21–27. 2019. View Article : Google Scholar : PubMed/NCBI
56	Ishiwata T, Bergmann U, Kornmann M, Lopez M, Beger HG and Korc M: Altered expression of insulin-like growth factor II receptor in human pancreatic cancer. Pancreas. 15:367–373. 1997. View Article : Google Scholar : PubMed/NCBI
57	Tian X, Hao K, Qin C, Xie K, Xie X and Yang Y: Insulin-like growth factor 1 receptor promotes the growth and chemoresistance of pancreatic cancer. Dig Dis Sci. 58:2705–2712. 2013. View Article : Google Scholar : PubMed/NCBI
58	Karna E, Surazynski A, Orłowski K, Łaszkiewicz J, Puchalski Z, Nawrat P and Pałka J: Serum and tissue level of insulin-like growth factor-I (IGF-I) and IGF-I binding proteins as an index of pancreatitis and pancreatic cancer. Int J Exp Pathol. 83:239–245. 2002. View Article : Google Scholar : PubMed/NCBI
59	Wan BS, Cheng M and Zhang L: Insulin-like growth factor 2 mRNA-binding protein 1 promotes cell proliferation via activation of AKT and is directly targeted by microRNA-494 in pancreatic cancer. World J Gastroenterol. 25:6063–6076. 2019. View Article : Google Scholar : PubMed/NCBI
60	Dahlem C, Barghash A, Puchas P, Haybaeck J and Kessler SM: The insulin-like growth factor 2 mRNA binding protein IMP2/IGF2BP2 is overexpressed and correlates with poor survival in pancreatic cancer. Int J Mol Sci. 20:32042019. View Article : Google Scholar
61	Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, Dekleva EN, Saunders T, Becerra CP, Tattersall IW, et al: Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 25:735–747. 2014. View Article : Google Scholar : PubMed/NCBI