Relations of miR-141-3p expression and its target gene with malignant profiles of hepatocellular carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LI Xuehua ¹ , XING Yuhui ² , LIU Zhiheng ¹ , JIANG Xiaohong ³ ,  HOU Xu ¹

1. Department of Hepatobiliary Surgery, Liaocheng People’s Hospital, Liaocheng, Shandong 252000, P. R. China;
2. Department of Obstetrics, Liaocheng People’s Hospital, Liaocheng, Shandong 252000, P. R. China;
3. Zhong Yuan Academy of Biological Medicine, Liaocheng People’s Hospital, Liaocheng, Shandong 252000, P. R. China;

Corresponding author：

HOU Xu, Email: aumg2009@126.com

Keywords：

hepatocellular carcinoma; Golgi protein 73; miR-141-3p

DOI：

10.7507/1007-9424.201905007

Video：

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Objective To investigate the expression of microRNA (miRNA, miR)-141-3p in hepatocellular carcinoma (HCC) tissues and its effect on proliferation and invasion of HCC.Methods Bioinformatics tools were used to predict putative miRs with search potential downstream gene–GP73, hsa-miR-141-3p was selected for further analysis and observations. A dual-luciferase reporter assay was performed to validate GP73 as a target of hsa-miR-141-3p. Real time PCR (qRT-PCR) or Western blot was performed to measure the expression level of miR-141-3p and GP73 in HCC and adjacent tissue. MTT, EdU, and Transwell were used to measure cell proliferation and migration.Results It was identified that the expression level of miR-141-3p was significantly lower in the HCC tissues than that of adjacent tissues (P<0.05), but different in GP73 mRNA and its protein (P<0.05). Clinical analysis indicated that decreased miR-141-3p expression was significantly correlated with advanced tumor grade, advanced TNM stage, and vascular invasion (P<0.05). MTT assay showed that the absorbance (A) value of Huh-7 cells transfected with miR-141-3p overexpression plasmid was significantly decreased compared with the miR-negative control (NC) group (transfected empty plasmid) and the blank control group (P<0.05).The EdU detection results showed that the ratio of EdU positive cells in Huh-7 and MHCC-97H cells were lower than those in the blank control group and the miR-NC group after transfection of miR-141-3p (P<0.05). Transwell test found that after transfection of miR-141-3p, the number of invading cells and the number of migrated cells in MHCC-97H cells were lower than those in the blank control group and the miR-NC group (P<0.05). The results of cytological function recovery experiments showed that the number of invading cells and the number of migrated cells in MHCC-97H cells of miR-141-3p+GP73 group were lower than those in blank control group and miR-NC group (P<0.05), but higher than those of the miR-141-3p group and miR-141-3p+GP73-NC group (P<0.05).Conclusions The present study revealed that miR-141-3p is reduced in HCC tissues. Additionally, GP73 expression levels are negatively correlated to miR-141-3p in HCC tissues, and that is associated with the progression of HCC. Overexpression of miR-141-3p significantly inhibit proliferation, invasion, and migration of HCC cells.Reversal of partial inhibition of miR-141-3p can be achieved by restoring the expression of the GP73 gene without the 3′ untranslated region (UTR).

Citation： LI Xuehua, XING Yuhui, LIU Zhiheng, JIANG Xiaohong, HOU Xu. Relations of miR-141-3p expression and its target gene with malignant profiles of hepatocellular carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2019, 26(10): 1175-1183. doi: 10.7507/1007-9424.201905007 Copy

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4.	Mao Y, Yang H, Xu H, et al. Golgi protein 73 (GOLPH2) is a valuable serum marker for hepatocellular carcinoma. Gut, 2010, 59(12): 1687-1693.
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9.	代智, 杨怡. 肝癌诊断标志物的新进展及应用. 中国普外基础与临床杂志, 2018, 25(4): 391-395.
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13.	Korpal M, Kang Y. The emerging role of miR-200 family of microRNAs in epithelial-mesenchymal transition and cancer metastasis. RNA Biol, 2008, 5(3): 115-119.
14.	Dhayat SA, Hüsing A, Senninger N, et al. Circulating microRNA-200 family as diagnostic marker in hepatocellular carcinoma. PLoS One, 2015, 10(10): e0140066.
15.	Khraiwesh B, Arif MA, Seumel GI, et al. Transcriptional control of gene expression by microRNAs. Cell, 2010, 140(1): 111-122.
16.	Llave C, Xie Z, Kasschau KD, et al. Cleavage of scarecrow-like mrna targets directed by a class of arabidopsis miRNA. Science, 2002, 297(5589): 2053-2056.
17.	Liep J, Kilic E, Meyer HA, et al. Cooperative effect of miR-141-3p and miR-145-5p in the regulation of targets in clear cell renal cell carcinoma. PLoS One, 2016, 11(6): e0157801.
18.	Zuo QF, Zhang R, Li BS, et al. MicroRNA-141 inhibits tumor growth and metastasis in gastric cancer by directly targeting transcriptional co-activator with PDZ-binding motif, TAZ. Cell Death Dis, 2015, 6(1): e1623.
19.	Li JZ, Li J, Wang HQ, et al. MiR-141-3p promotes prostate cancer cell proliferation through inhibiting kruppel-like factor-9 expression. Biochem Biophys Res Commun, 2017, 482(4): 1381-1386.
20.	Kim MK, Moon YA, Song CK, et al. Tumor-suppressing miR-141 gene complex-loaded tissue-adhesive glue for the locoregional treatment of hepatocellular carcinoma. Theranostics, 2018, 8(14): 3891-3901.
21.	Zheng L, Xu M, Xu J, et al. ELF3 promotes epithelial-mesenchymal transition by protecting ZEB1 from miR-141-3p-mediated silencing in hepatocellular carcinoma. Cell Death Dis, 2018, 9(3): 387.
22.	Huang XY, Huang ZL, Xu YH, et al. Comprehensive circular RNA profiling reveals the regulatory role of the circRNA-100338/miR-141-3p pathway in hepatitis B-related hepatocellular carcinoma. Sci Rep, 2017, 7(1): 5428.
23.	Wu L, Pan C, Wei X, et al. lncRNA KRAL reverses 5-fluorouracil resistance in hepatocellular carcinoma cells by acting as a ceRNA against miR-141. Cell Commun Signal, 2018, 16(1): 47.
24.	Lou G, Dong X, Xia C, et al. Direct targeting sperm-associated antigen 9 by miR-141 influences hepatocellular carcinoma cell growth and metastasis via JNK pathway. J Exp Clin Cancer Res, 2016, 35: 14.
25.	Liu Y, Ding Y, Huang J, et al. MiR-141 suppresses the migration and invasion of HCC cells by targeting Tiam1. PLoS One, 2014, 9(2): e88393.

1. Zhu AX. Molecularly targeted therapy for advanced hepatocellular carcinoma in 2012: current status and future perspectives. Semin Oncol, 2012, 39(4): 493-502.
2. Psyrri A, Arkadopoulos N, Vassilakopoulou M, et al. Pathways and targets in hepatocellular carcinoma. Expert Rev Anticancer Ther, 2012, 12(10): 1347-1357.
3. Riener MO, Stenner F, Liewen H, et al. Golgi phosphoprotein 2 (GOLPH2) expression in liver tumors and its value as a serum marker in hepatocellular carcinomas. Hepatology, 2009, 49(5): 1602-1609.
4. Mao Y, Yang H, Xu H, et al. Golgi protein 73 (GOLPH2) is a valuable serum marker for hepatocellular carcinoma. Gut, 2010, 59(12): 1687-1693.
5. Chen X, Wang Y, Tao J, et al. mTORC1 up-regulates GP73 to promote proliferation and migration of hepatocellular carcinoma cells and growth of xenograft tumors in mice. Gastroenterology, 2015, 149(3): 741-752.
6. Li Q, Ma Y, Xu W. High GOLPH3 expression is associated with poor prognosis and invasion of hepatocellular carcinoma. Mol Med Rep, 2015, 11(6): 4315-4320.
7. Hou X, Yang L, Jiang X, et al. Prognostic significance of golgi protein 73 in hepatocellular carcinoma after hepatectomy in the Chinese population: a meta-analysis. Int J Clin Exp Med, 2017, 10(1): 48-58.
8. George J, Patel T. Noncoding RNA as therapeutic targets for hepatocellular carcinoma. Semin Liver Dis, 2015, 35(1): 63-74.
9. 代智, 杨怡. 肝癌诊断标志物的新进展及应用. 中国普外基础与临床杂志, 2018, 25(4): 391-395.
10. Pan L, Huang S, He R, et al. Decreased expression and clinical significance of miR-148a in hepatocellular carcinoma tissues. Eur J Med Res, 2014, 19(1): 68.
11. Zhang S, Liu Q, Zhang Q, et al. MicroRNA-30a-5p suppresses proliferation, invasion and tumor growth of hepatocellular cancer cells via targeting FOXA1. Oncol Lett, 2017, 14(4): 5018-5026.
12. Liu CZ, Ye ZH, Ma J, et al. A qRT-PCR and gene functional enrichment study focused on downregulation of miR-141-3p in hepatocellular carcinoma and its clinicopathological significance. Technol Cancer Res Treat, 2017, 16(6): 835-849.
13. Korpal M, Kang Y. The emerging role of miR-200 family of microRNAs in epithelial-mesenchymal transition and cancer metastasis. RNA Biol, 2008, 5(3): 115-119.
14. Dhayat SA, Hüsing A, Senninger N, et al. Circulating microRNA-200 family as diagnostic marker in hepatocellular carcinoma. PLoS One, 2015, 10(10): e0140066.
15. Khraiwesh B, Arif MA, Seumel GI, et al. Transcriptional control of gene expression by microRNAs. Cell, 2010, 140(1): 111-122.
16. Llave C, Xie Z, Kasschau KD, et al. Cleavage of scarecrow-like mrna targets directed by a class of arabidopsis miRNA. Science, 2002, 297(5589): 2053-2056.
17. Liep J, Kilic E, Meyer HA, et al. Cooperative effect of miR-141-3p and miR-145-5p in the regulation of targets in clear cell renal cell carcinoma. PLoS One, 2016, 11(6): e0157801.
18. Zuo QF, Zhang R, Li BS, et al. MicroRNA-141 inhibits tumor growth and metastasis in gastric cancer by directly targeting transcriptional co-activator with PDZ-binding motif, TAZ. Cell Death Dis, 2015, 6(1): e1623.
19. Li JZ, Li J, Wang HQ, et al. MiR-141-3p promotes prostate cancer cell proliferation through inhibiting kruppel-like factor-9 expression. Biochem Biophys Res Commun, 2017, 482(4): 1381-1386.
20. Kim MK, Moon YA, Song CK, et al. Tumor-suppressing miR-141 gene complex-loaded tissue-adhesive glue for the locoregional treatment of hepatocellular carcinoma. Theranostics, 2018, 8(14): 3891-3901.
21. Zheng L, Xu M, Xu J, et al. ELF3 promotes epithelial-mesenchymal transition by protecting ZEB1 from miR-141-3p-mediated silencing in hepatocellular carcinoma. Cell Death Dis, 2018, 9(3): 387.
22. Huang XY, Huang ZL, Xu YH, et al. Comprehensive circular RNA profiling reveals the regulatory role of the circRNA-100338/miR-141-3p pathway in hepatitis B-related hepatocellular carcinoma. Sci Rep, 2017, 7(1): 5428.
23. Wu L, Pan C, Wei X, et al. lncRNA KRAL reverses 5-fluorouracil resistance in hepatocellular carcinoma cells by acting as a ceRNA against miR-141. Cell Commun Signal, 2018, 16(1): 47.
24. Lou G, Dong X, Xia C, et al. Direct targeting sperm-associated antigen 9 by miR-141 influences hepatocellular carcinoma cell growth and metastasis via JNK pathway. J Exp Clin Cancer Res, 2016, 35: 14.
25. Liu Y, Ding Y, Huang J, et al. MiR-141 suppresses the migration and invasion of HCC cells by targeting Tiam1. PLoS One, 2014, 9(2): e88393.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Relations of miR-141-3p expression and its target gene with malignant profiles of hepatocellular carcinoma

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