MicroRNA‑766 inhibits papillary thyroid cancer progression by directly targeting insulin receptor substrate 2 and regulating the PI3K/Akt pathway Retraction in /10.3892/ijo.2022.5376

Zhao,Jianjie; Li,Zhirong; Chen,Yi; Zhang,Shu; Guo,Lingji; Gao,Bo; Jiang,Yan; Tian,Wuguo; Hao,Shuai; Zhang,Xiaohua

doi:10.3892/ijo.2018.4615

MicroRNA‑766 inhibits papillary thyroid cancer progression by directly targeting insulin receptor substrate 2 and regulating the PI3K/Akt pathway

Retraction in: /10.3892/ijo.2022.5376

Authors:
- Jianjie Zhao
- Zhirong Li
- Yi Chen
- Shu Zhang
- Lingji Guo
- Bo Gao
- Yan Jiang
- Wuguo Tian
- Shuai Hao
- Xiaohua Zhang
View Affiliations

Affiliations: Department of Breast and Thyroid Surgery, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, P.R. China
Published online on: November 1, 2018 https://doi.org/10.3892/ijo.2018.4615
Pages: 315-325

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

MicroRNAs (miRNAs/miRs) are widely dysregulated in papillary thyroid cancer (PTC). Dysregulated miRNAs, together with their target genes, comprise a complex network that has been implicated in the regulation of PTC pathogenesis. Further knowledge of the functional roles of aberrantly expressed miRNAs in PTC, and the underlying molecular mechanisms, may assist in the identification of novel therapeutic targets. miR‑766 has been well studied in human cancer; however, the expression status, specific roles and regulatory mechanisms of miR‑766 in PTC remain unclear. The present study aimed to detect miR‑766 expression in PTC tissues and cell lines, to explore the biological roles of miR‑766 in the malignant biological behaviors of PTC cells, and to determine the underlying mechanism of action of miR‑766 in PTC cells. The results revealed that miR‑766 was downregulated in PTC tissues and cell lines, and its downregulation was strongly associated with TNM stage and lymph node metastasis. Overexpression of miR‑766 inhibited PTC cell proliferation, colony formation, migration and invasion, promoted cell apoptosis and reduced tumor growth in vivo. Mechanistically, insulin receptor substrate 2 (IRS2) was identified as a direct target of miR‑766 in PTC cells. IRS2 was upregulated in PTC tissues, and this was inversely correlated with miR‑766 expression. Inhibition of IRS2 simulated the tumor suppressor activity of miR‑766 in PTC cells. Restoration of IRS2 expression negated the tumor‑suppressing effects of miR‑766 overexpression on PTC cells. Notably, miR‑766 directly targeted IRS2 to inhibit activation of the phosphoinositide 3‑kinase (PI3K)/protein kinase B (Akt) pathway in PTC cells in vitro and in vivo. Overall, these findings indicated that miR‑766 may inhibit the malignant biological behaviors of PTC cells by directly targeting IRS2 and regulating the PI3K/Akt pathway, thus suggesting that this miRNA may be a promising therapeutic target for PTC.

View Figures

View References

1	Xiang D, Xie L, Xu Y, Li Z, Hong Y and Wang P: Papillary thyroid microcarcinomas located at the middle part of the middle third of the thyroid gland correlates with the presence of neck metastasis. Surgery. 157:526–533. 2015. View Article : Google Scholar
2	Kim HY, Park WY, Lee KE, Park WS, Chung YS, Cho SJ and Youn YK: Comparative analysis of gene expression profiles of papillary thyroid microcarcinoma and papillary thyroid carcinoma. J Cancer Res Ther. 6:452–457. 2010. View Article : Google Scholar
3	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
4	Ye Y, Zhuang J, Wang G, He S, Ni J and Xia W: MicroRNA-139 targets fibronectin 1 to inhibit papillary thyroid carcinoma progression. Oncol Lett. 14:7799–7806. 2017.PubMed/NCBI
5	Catalano MG, Poli R, Pugliese M, Fortunati N and Boccuzzi G: Emerging molecular therapies of advanced thyroid cancer. Mol Aspects Med. 31:215–226. 2010. View Article : Google Scholar : PubMed/NCBI
6	Peng XG, Chen ZF, Zhang KJ, Wang PG, Liu ZM, Chen ZJ, Hou GY and Niu M: VEGF Trapon inhibits tumor growth in papillary thyroid carcinoma. Eur Rev Med Pharmacol Sci. 19:235–240. 2015.PubMed/NCBI
7	Fagin JA and Wells SA Jr: Biologic and clinical perspectives on thyroid cancer. N Engl J Med. 375:23072016. View Article : Google Scholar : PubMed/NCBI
8	Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI
9	He L and Hannon GJ: MicroRNAs: Small RNAs with a big role in gene regulation. Nat Rev Genet. 5:522–531. 2004. View Article : Google Scholar : PubMed/NCBI
10	Dragomir M, Mafra ACP, Dias SMG, Vasilescu C and Calin GA: Using microRNA Networks to understand cancer. Int J Mol Sci. 19:192018. View Article : Google Scholar
11	Iorio MV, Casalini P, Tagliabue E, Ménard S and Croce CM: MicroRNA profiling as a tool to understand prognosis, therapy response and resistance in breast cancer. Eur J Cancer. 44:2753–2759. 2008. View Article : Google Scholar : PubMed/NCBI
12	Aragon Han P, Weng CH, Khawaja HT, Nagarajan N, Schneider EB, Umbricht CB, Witwer KW and Zeiger MA: MicroRNA expression and association with clinicopathologic features in papillary thyroid cancer: A systematic review. Thyroid. 25:1322–1329. 2015. View Article : Google Scholar : PubMed/NCBI
13	Yi R, Li Y, Wang FL, Miao G, Qi RM and Zhao YY: MicroRNAs as diagnostic and prognostic biomarkers in colorectal cancer. World J Gastrointest Oncol. 8:330–340. 2016. View Article : Google Scholar : PubMed/NCBI
14	Uddin A and Chakraborty S: Role of miRNAs in lung cancer. J Cell Physiol. Apr 20–2018.Epub ahead of print. View Article : Google Scholar
15	Ahir BK, Ozer H, Engelhard HH and Lakka SS: MicroRNAs in glioblastoma pathogenesis and therapy: A comprehensive review. Crit Rev Oncol Hematol. 120:22–33. 2017. View Article : Google Scholar : PubMed/NCBI
16	Homami A and Ghazi F: MicroRNAs as biomarkers associated with bladder cancer. Med J Islam Repub Iran. 30:4752016.
17	Mutalib NS, Yusof AM, Mokhtar NM, Harun R, Muhammad R and Jamal R: MicroRNAs and lymph node metastasis in papillary thyroid cancers. Asian Pac J Cancer Prev. 17:25–35. 2016. View Article : Google Scholar : PubMed/NCBI
18	Lee JC, Gundara JS, Glover A, Serpell J and Sidhu SB: MicroRNA expression profiles in the management of papillary thyroid cancer. Oncologist. 19:1141–1147. 2014. View Article : Google Scholar : PubMed/NCBI
19	Zhu G, Xie L and Miller D: Expression of microRNAs in thyroid carcinoma. Methods Mol Biol. 1617:261–280. 2017. View Article : Google Scholar : PubMed/NCBI
20	Fu YT, Zheng HB, Zhang DQ, Zhou L and Sun H: MicroRNA-1266 suppresses papillary thyroid carcinoma cell metastasis and growth via targeting FGFR2. Eur Rev Med Pharmacol Sci. 22:3430–3438. 2018.PubMed/NCBI
21	Wang R, Ma Q, Ji L, Yao Y, Ma M and Wen Q: miR-622 suppresses tumor formation by directly targeting VEGFA in papillary thyroid carcinoma. OncoTargets Ther. 11:1501–1509. 2018. View Article : Google Scholar
22	Ma S, Jia W and Ni S: miR-199a-5p inhibits the progression of papillary thyroid carcinoma by targeting SNAI1. Biochem Biophys Res Commun. 497:181–186. 2018. View Article : Google Scholar : PubMed/NCBI
23	Chen C, Xue S, Zhang J, Chen W, Gong D, Zheng J, Ma J, Xue W, Chen Y, Zhai W, et al: DNA-methylation-mediated repression of miR-766-3p promotes cell proliferation via targeting SF2 expression in renal cell carcinoma. Int J Cancer. 141:1867–1878. 2017. View Article : Google Scholar : PubMed/NCBI
24	Li X, Shi Y, Yin Z, Xue X and Zhou B: An eight-miRNA signature as a potential biomarker for predicting survival in lung adenocarcinoma. J Transl Med. 12:1592014. View Article : Google Scholar : PubMed/NCBI
25	Suresh R, Sethi S, Ali S, Giorgadze T and Sarkar FH: Differential expression of microRNAs in papillary thyroid carcinoma and their Role in Racial Disparity. J Cancer Sci Ther. 7:145–154. 2015.PubMed/NCBI
26	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
27	Dong S, Meng X, Xue S, Yan Z, Ren P and Liu J: microRNA-141 inhibits thyroid cancer cell growth and metastasis by targeting insulin receptor substrate 2. Am J Transl Res. 8:1471–1481. 2016.PubMed/NCBI
28	Landis J and Shaw LM: Insulin receptor substrate 2-mediated phosphatidylinositol 3-kinase signaling selectively inhibits glycogen synthase kinase 3β to regulate aerobic glycolysis. J Biol Chem. 289:18603–18613. 2014. View Article : Google Scholar : PubMed/NCBI
29	Mercado-Matos J, Clark JL, Piper AJ, Janusis J and Shaw LM: Differential involvement of the microtubule cytoskeleton in insulin receptor substrate 1 (IRS-1) and IRS-2 signaling to AKT determines the response to microtubule disruption in breast carcinoma cells. J Biol Chem. 292:7806–7816. 2017. View Article : Google Scholar : PubMed/NCBI
30	Jeong SH and Lim DS: Insulin receptor substrate 2: A bridge between Hippo and AKT pathways. BMB Rep. 51:209–210. 2018. View Article : Google Scholar : PubMed/NCBI
31	Hu J, Li C, Liu C, Zhao S, Wang Y and Fu Z: Expressions of miRNAs in papillary thyroid carcinoma and their associations with the clinical characteristics of PTC. Cancer Biomark. 18:87–94. 2017. View Article : Google Scholar : PubMed/NCBI
32	Yoruker EE, Terzioglu D, Teksoz S, Uslu FE, Gezer U and Dalay N: MicroRNA expression profiles in papillary thyroid carcinoma, benign thyroid nodules and healthy controls. J Cancer. 7:803–809. 2016. View Article : Google Scholar : PubMed/NCBI
33	Hu Y, Wang H, Chen E, Xu Z, Chen B and Lu G: Candidate microRNAs as biomarkers of thyroid carcinoma: A systematic review, meta-analysis, and experimental validation. Cancer Med. 5:2602–2614. 2016. View Article : Google Scholar : PubMed/NCBI
34	Oh K and Lee DS: In vivo validation of metastasis-regulating microRNA-766 in human triple-negative breast cancer cells. Lab Anim Res. 33:256–263. 2017. View Article : Google Scholar : PubMed/NCBI
35	Li YC, Li CF, Chen LB, Li DD, Yang L, Jin JP and Zhang B: MicroRNA-766 targeting regulation of SOX6 expression promoted cell proliferation of human colorectal cancer. OncoTargets Ther. 8:2981–2988. 2015. View Article : Google Scholar
36	Afgar A, Fard-Esfahani P, Mehrtash A, Azadmanesh K, Khodarahmi F, Ghadir M and Teimoori-Toolabi L: miR-339 and especially miR-766 reactivate the expression of tumor suppressor genes in colorectal cancer cell lines through DNA methyltransferase 3B gene inhibition. Cancer Biol Ther. 17:1126–1138. 2016. View Article : Google Scholar : PubMed/NCBI
37	White MF: IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab. 283:E413–E422. 2002. View Article : Google Scholar : PubMed/NCBI
38	Day E, Poulogiannis G, McCaughan F, Mulholland S, Arends MJ, Ibrahim AE and Dear PH: IRS2 is a candidate driver oncogene on 13q34 in colorectal cancer. Int J Exp Pathol. 94:203–211. 2013.PubMed/NCBI
39	Ma Y, Zhang H, He X, Song H, Qiang Y, Li Y, Gao J and Wang Z: miR-106a^* inhibits the proliferation of renal carcinoma cells by targeting IRS-2. Tumour Biol. 36:8389–8398. 2015. View Article : Google Scholar : PubMed/NCBI
40	Xu H, Lee MS, Tsai PY, Adler AS, Curry NL, Challa S, Freinkman E, Hitchcock DS, Copps KD, White MF, et al: Ablation of insulin receptor substrates 1 and 2 suppresses Kras-driven lung tumorigenesis. Proc Natl Acad Sci USA. 115:4228–4233. 2018. View Article : Google Scholar
41	Porter HA, Perry A, Kingsley C, Tran NL and Keegan AD: IRS1 is highly expressed in localized breast tumors and regulates the sensitivity of breast cancer cells to chemotherapy, while IRS2 is highly expressed in invasive breast tumors. Cancer Lett. 338:239–248. 2013. View Article : Google Scholar : PubMed/NCBI
42	Zhang P, Shao G, Lin X, Liu Y and Yang Z: miR-338-3p inhibits the growth and invasion of non-small cell lung cancer cells by targeting IRS2. Am J Cancer Res. 7:53–63. 2017.PubMed/NCBI
43	de Melo Campos P, Machado-Neto JA, Eide CA, Savage SL, Scopim-Ribeiro R, da Silva Souza Duarte, Favaro PA, Lorand-Metze I, Costa FF, Tognon CE, et al: IRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in JAK2V617F-positive myeloproliferative neoplasms. Oncotarget. 7:6948–6959. 2016.PubMed/NCBI
44	Liu H, Ren G, Zhu L, Liu X and He X: The upregulation of miRNA-146a inhibited biological behaviors of ESCC through inhibition of IRS2. Tumour Biol. 37:4641–4647. 2016. View Article : Google Scholar