Expression of microRNA 638 and sex-determining region Y-box 2 in hepatocellular carcinoma: Association between clinicopathological features and prognosis

  • Authors:
    • Weikang Ye
    • Jieke Li
    • Guan Fang
    • Xiupeng Cai
    • Yan Zhang
    • Chaojun Zhou
    • Lei Chen
    • Wenjun Yang
  • View Affiliations

  • Published online on: March 8, 2018     https://doi.org/10.3892/ol.2018.8208
  • Pages: 7255-7264
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Abstract

The aim of the present study was to determine the expression profile of microRNA 638 (miR-638) and sex-determining region Y-box 2 (SOX2) in hepatocellular carcinoma (HCC), and to investigate their association with clinicopathological features and survival. Reverse transcription‑quantitative polymerase chain reaction analysis was used to investigate miR‑638 and SOX2 expression in 78 patients with HCC. Western blot and immunohistochemical analyses were performed in order to determine SOX2 protein expression in HCC samples. Combined with the clinical postoperative follow‑up data, the expression of miR‑638 and SOX2 and the association between this and the prognostic values of patients with HCC were statistically analyzed. The results of the present study confirmed that miR‑638 expression in tumor tissues was significantly downregulated (P<0.001), while SOX2 expression was significantly increased, compared with healthy control tissues (P<0.05). In addition, a significant inverse correlation between miR‑638 and SOX2 expression was also observed in the HCC tissues (r=‑0.675; P<0.05). Clinicopathological correlation analysis demonstrated that reduced miR‑638 and elevated SOX2 expression was significantly associated with the Tumor‑Node‑Metastasis stage and portal vascular invasion (P<0.05). However, no significant differences were observed in other clinicopathological features, including age, sex, tumor size, tumor differentiation and hepatitis status (P>0.05). Notably, follow‑up analysis revealed that patients with HCC with low miR‑638 expression and high SOX2 expression tended to have a significantly shorter postoperative survival time (P<0.001). It was concluded that miR‑638 may serve a vital role in the occurrence and progression of HCC by regulating SOX2 expression and thus, that miR‑638 and SOX2 may be critical as novel diagnostic and prognostic biomarkers for HCC.

References

1 

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Bruix J and Sherman M: American Association for the Study of Liver Diseases: Management of hepatocellular carcinoma: An update. Hepatology. 53:1020–1022. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Hsu CY, Liu PH, Hsia CY, Lee YH, Nagaria TS, Lee RC, Lin HC and Huo TI: Surgical resection is better than transarterial chemoembolization for patients with hepatocellular carcinoma beyond the milan criteria: A prognostic nomogram study. Ann Surg Oncol. 23:994–1002. 2016. View Article : Google Scholar : PubMed/NCBI

4 

Tremosini S, Reig M, de Lope CR, Forner A and Bruix J: Treatment of early hepatocellular carcinoma: Towards personalized therapy. Dig Liver Dis. 42 Suppl 3:S242–S248. 2010. View Article : Google Scholar : PubMed/NCBI

5 

Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S, Sugawara Y, Minagawa M, Takayama T, Kawasaki S and Makuuchi M: Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 38:200–207. 2003. View Article : Google Scholar : PubMed/NCBI

6 

Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI

7 

Lin SL, Chang DC, Ying SY, Leu D and Wu DT: MicroRNA miR-302 inhibits the tumorigenecity of human pluripotent stem cells by coordinate suppression of the CDK2 and CDK4/6 cell cycle pathways. Cancer Res. 70:9473–9482. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Wang Z, Yin B, Wang B, Ma Z, Liu W and Lv G: MicroRNA-210 promotes proliferation and invasion of peripheral nerve sheath tumor cells targeting EFNA3. Oncol Res. 21:145–154. 2013. View Article : Google Scholar : PubMed/NCBI

9 

Tome M, López-Romero P, Albo C, Sepúlveda JC, Fernández-Gutiérrez B, Dopazo A, Bernad A and González MA: miR-335 orchestrates cell proliferation, migration and differentiation in human mesenchymal stem cells. Cell Death Differ. 18:985–995. 2011. View Article : Google Scholar : PubMed/NCBI

10 

Zhang Y, He X, Liu Y, Ye Y, Zhang H, He P, Zhang Q, Dong L, Liu Y and Dong J: microRNA-320a inhibits tumor invasion by targeting neuropilin 1 and is associated with liver metastasis in colorectal cancer. Oncol Rep. 27:685–694. 2012.PubMed/NCBI

11 

Ma D, Tao X, Gao F, Fan C and Wu D: miR-224 functions as an onco-miRNA in hepatocellular carcinoma cells by activating AKT signaling. Oncol Lett. 4:483–488. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI

13 

Xu J, Li J, Zheng TH, Bai L and Liu ZJ: MicroRNAs in the occurrence and development of primary hepatocellular carcinoma. Adv Clin Exp Med. 25:971–975. 2016. View Article : Google Scholar : PubMed/NCBI

14 

Zhang J, Fei B, Wang Q, Song M, Yin Y, Zhang B, Ni S, Guo W, Bian Z, Quan C, et al: MicroRNA-638 inhibits cell proliferation, invasion and regulates cell cycle by targeting tetraspanin 1 in human colorectal carcinoma. Oncotarget. 5:12083–12096. 2014.PubMed/NCBI

15 

Zhang J, Bian Z, Zhou J, Song M, Liu Z, Feng Y, Zhe L, Zhang B, Yin Y and Huang Z: MicroRNA-638 inhibits cell proliferation by targeting phospholipase D1 in human gastric carcinoma. Protein Cell. 6:680–688. 2015. View Article : Google Scholar : PubMed/NCBI

16 

Tan X, Peng J, Fu Y, An S, Rezaei K, Tabbara S, Teal CB, Man YG, Brem RF and Fu SW: miR-638 mediated regulation of BRCA1 affects DNA repair and sensitivity to UV and cisplatin in triple-negative breast cancer. Breast Cancer Res. 16:4352014. View Article : Google Scholar : PubMed/NCBI

17 

Wang XX, Liu J, Tang YM, Hong L, Zeng Z and Tan GH: MicroRNA-638 inhibits cell proliferation by targeting suppress PIM1 expression in human osteosarcoma. Tumour Biol. Jan 3–2017.(Epub ahead of print).

18 

Bhattacharya A, Schmitz U, Raatz Y, Schönherr M, Kottek T, Schauer M, Franz S, Saalbach A, Anderegg U, Wolkenhauer O, et al: miR-638 promotes melanoma metastasis and protects melanoma cells from apoptosis and autophagy. Oncotarget. 6:2966–2980. 2015. View Article : Google Scholar : PubMed/NCBI

19 

Fong H, Hohenstein KA and Donovan PJ: Regulation of self-renewal and pluripotency by Sox2 in human embryonic stem cells. Stem cells. 26:1931–1938. 2008. View Article : Google Scholar : PubMed/NCBI

20 

Leis O, Eguiara A, Lopez-Arribillaga E, Alberdi MJ, Hernandez-Garcia S, Elorriaga K, Pandiella A, Rezola R and Martin AG: Sox2 expression in breast tumours and activation in breast cancer stem cells. Oncogene. 31:1354–1365. 2012. View Article : Google Scholar : PubMed/NCBI

21 

Neumann J, Bahr F, Horst D, Kriegl L, Engel J, Luque RM, Gerhard M, Kirchner T and Jung A: SOX2 expression correlates with lymph-node metastases and distant spread in right-sided colon cancer. BMC Cancer. 11:5182011. View Article : Google Scholar : PubMed/NCBI

22 

Jia X, Li X, Xu Y, Zhang S, Mou W, Liu Y, Liu Y, Lv D, Liu CH, Tan X, et al: SOX2 promotes tumorigenesis and increases the anti-apoptotic property of human prostate cancer cell. J Mol Cell Biol. 3:230–238. 2011. View Article : Google Scholar : PubMed/NCBI

23 

Nakatsugawa M, Takahashi A, Hirohashi Y, Torigoe T, Inoda S, Murase M, Asanuma H, Tamura Y, Morita R, Michifuri Y, et al: SOX2 is overexpressed in stem-like cells of human lung adenocarcinoma and augments the tumorigenicity. Lab Invest. 91:1796–1804. 2011. View Article : Google Scholar : PubMed/NCBI

24 

Chen Y, Huang Y, Zhu L, Chen M, Huang Y, Zhang J, He S, Li A, Chen R and Zhou J: SOX2 inhibits metastasis in gastric cancer. J Cancer Res Clin Oncol. 142:1221–1230. 2016. View Article : Google Scholar : PubMed/NCBI

25 

Cho YY, Kim DJ, Lee HS, Jeong CH, Cho EJ, Kim MO, Byun S, Lee KY, Yao K, Carper A, et al: Autophagy and cellular senescence mediated by Sox2 suppress malignancy of cancer cells. PLoS One. 8:e571722013. View Article : Google Scholar : PubMed/NCBI

26 

Wang S, Tie J, Wang R, Hu F, Gao L, Wang W, Wang L, Li Z, Hu S, Tang S, et al: SOX2, a predictor of survival in gastric cancer, inhibits cell proliferation and metastasis by regulating PTEN. Cancer Lett. 358:210–219. 2015. View Article : Google Scholar : PubMed/NCBI

27 

Ma K, Pan X, Fan P, He Y, Gu J, Wang W, Zhang T, Li Z and Luo X: Loss of miR-638 in vitro promotes cell invasion and a mesenchymal-like transition by influencing SOX2 expression in colorectal carcinoma cells. Mol Cancer. 13:1182014. View Article : Google Scholar : PubMed/NCBI

28 

Xia Y, Wu Y, Liu B, Wang P and Chen Y: Downregulation of miR-638 promotes invasion and proliferation by regulating SOX2 and induces EMT in NSCLC. FEBS Lett. 588:2238–2245. 2014. View Article : Google Scholar : PubMed/NCBI

29 

Cheng J, Chen Y, Zhao P, Liu X, Dong J, Li J, Huang C, Wu R and Lv Y: Downregulation of miRNA-638 promotes angiogenesis and growth of hepatocellular carcinoma by targeting VEGF. Oncotarget. 7:30702–30711. 2016.PubMed/NCBI

30 

Zhang Y, Zhang D, Jiang J and Dong L: Loss of miR-638 promotes invasion and epithelial-mesenchymal transition by targeting SOX2 in hepatocellular carcinoma. Oncol Rep. 37:323–332. 2017. View Article : Google Scholar : PubMed/NCBI

31 

Poon RT and Fan ST: Evaluation of the new AJCC/UICC staging system for hepatocellular carcinoma after hepatic resection in Chinese patients. Surg Oncol Clin N Am. 12(35–50): viii2003.

32 

Li ZS and Li Q: The latest 2010 WHO classification of tumors of digestive system. Zhonghua Bing Li Xue Za Zhi. 40:351–354. 2011.(In Chinese). PubMed/NCBI

33 

Flejou JF: WHO Classification of digestive tumors: The fourth edition. Ann Pathol. 31 5 Suppl:S27–S31. 2011.PubMed/NCBI

34 

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

35 

Zhang X, Wei J, Zhou L, Zhou C, Shi J, Yuan Q, Yang M and Lin D: A functional BRCA1 coding sequence genetic variant contributes to risk of esophageal squamous cell carcinoma. Carcinogenesis. 34:2309–2313. 2013. View Article : Google Scholar : PubMed/NCBI

36 

Zhao LY, Yao Y, Han J, Yang J, Wang XF, Tong DD, Song TS, Huang C and Shao Y: miR-638 suppresses cell proliferation in gastric cancer by targeting Sp2. Dig Dis Sci. 59:1743–1753. 2014. View Article : Google Scholar : PubMed/NCBI

37 

Tay Y, Tan SM, Karreth FA, Lieberman J and Pandolfi PP: Characterization of dual PTEN and p53-targeting microRNAs identifies microRNA-638/Dnm2 as a two-hit oncogenic locus. Cell Rep. 8:714–722. 2014. View Article : Google Scholar : PubMed/NCBI

38 

Li D, Wang Q, Liu C, Duan H, Zeng X, Zhang B, Li X, Zhao J, Tang S, Li Z, et al: Aberrant expression of miR-638 contributes to benzo(a)pyrene-induced human cell transformation. Toxicol Sci. 125:382–391. 2012. View Article : Google Scholar : PubMed/NCBI

39 

Wegner M: From head to toes: The multiple facets of Sox proteins. Nucleic Acids Res. 27:1409–1420. 1999. View Article : Google Scholar : PubMed/NCBI

40 

Ishii Y, Rex M, Scotting PJ and Yasugi S: Region-specific expression of chicken Sox2 in the developing gut and lung epithelium: Regulation by epithelial-mesenchymal interactions. Dev Dyn. 213:464–475. 1998. View Article : Google Scholar : PubMed/NCBI

41 

Liu K, Lin B, Zhao M, Yang X, Chen M, Gao A, Liu F, Que J and Lan X: The multiple roles for Sox2 in stem cell maintenance and tumorigenesis. Cell Signal. 25:1264–1271. 2013. View Article : Google Scholar : PubMed/NCBI

42 

Honing J, Pavlov KV, Meijer C, Smit JK, Boersma-van Ek W, Karrenbeld A, Burgerhof JG, Kruyt FA and Plukker JT: Loss of CD44 and SOX2 expression is correlated with a poor prognosis in esophageal adenocarcinoma patients. Ann Surg Oncol. 21 Suppl 4:S657–S664. 2014. View Article : Google Scholar : PubMed/NCBI

43 

Lundberg IV, Löfgren Burström A, Edin S, Eklöf V, Öberg Å, Stenling R, Palmqvist R and Wikberg ML: SOX2 expression is regulated by BRAF and contributes to poor patient prognosis in colorectal cancer. PLoS One. 9:e1019572014. View Article : Google Scholar : PubMed/NCBI

44 

Li J, Du L, Yang Y, Wang C, Liu H, Wang L, Zhang X, Li W, Zheng G and Dong Z: MiR-429 is an independent prognostic factor in colorectal cancer and exerts its anti-apoptotic function by targeting SOX2. Cancer Lett. 329:84–90. 2013. View Article : Google Scholar : PubMed/NCBI

45 

Otsubo T, Akiyama Y, Hashimoto Y, Shimada S, Goto K and Yuasa Y: MicroRNA-126 inhibits SOX2 expression and contributes to gastric carcinogenesis. PLoS One. 6:e166172011. View Article : Google Scholar : PubMed/NCBI

46 

Wang Z, Qiao Q, Chen M, Li X, Wang Z, Liu C and Xie Z: miR-625 down-regulation promotes proliferation and invasion in esophageal cancer by targeting Sox2. FEBS Lett. 588:915–921. 2014. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
APA
Ye, W., Li, J., Fang, G., Cai, X., Zhang, Y., Zhou, C. ... Yang, W. (2018). Expression of microRNA 638 and sex-determining region Y-box 2 in hepatocellular carcinoma: Association between clinicopathological features and prognosis. Oncology Letters, 15, 7255-7264. https://doi.org/10.3892/ol.2018.8208
MLA
Ye, W., Li, J., Fang, G., Cai, X., Zhang, Y., Zhou, C., Chen, L., Yang, W."Expression of microRNA 638 and sex-determining region Y-box 2 in hepatocellular carcinoma: Association between clinicopathological features and prognosis". Oncology Letters 15.5 (2018): 7255-7264.
Chicago
Ye, W., Li, J., Fang, G., Cai, X., Zhang, Y., Zhou, C., Chen, L., Yang, W."Expression of microRNA 638 and sex-determining region Y-box 2 in hepatocellular carcinoma: Association between clinicopathological features and prognosis". Oncology Letters 15, no. 5 (2018): 7255-7264. https://doi.org/10.3892/ol.2018.8208