Enhanced sensitivity of hepatocellular carcinoma cell line SMMC-7721 to oxaliplatin by silencing forkhead box Q1 gene with RNA interference technology_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

DENG Dawei ^1,2 , WU Bin ^1,2 , YAN Shu ^1,2 , ZHANG Guangnian ^1,2 , LAN Chuan ^1,2 , YI Pengsheng ^1,2 , ZENG Lijuan ³ ,  LI Jianshui ^1,2

1. Institute of Hepato-Biliary-Pancreas and Intestinal Disease, North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;
2. Department of Hepatobiliary Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;
3. Information Center, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;

Corresponding author：

LI Jianshui, Email: ljs2005doctor@126.com

Keywords：

hepatocellular carcinoma; forkhead box Q1; oxaliplatin; sensitizing effect

DOI：

10.7507/1007-9424.201708067

Video：

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Objective To observe the effect of forkhead box Q1(FOXQ1) short hairpin RNA (shRNA) on sensitivity of oxaliplatin chemotherapy in hepatpcellular carcinoma cell line SMMC-7721. Methods ① Complementary shRNA oligonucleotides targeting the FOXQ1 gene and negative control-shRNA were designed and inserted into lentiviral vector. shRNA lentivirus vectors were transfected into SMMC-7721 cells and the lentivirus vector with the best silencing effect was screened. ② SMMC-7721 cells were divided into interference group (SMMC-7721 cells were transfected with FOXQ1-shRNA-1), negative control group (SMMC-7721 cells were transfected with negative control-shRNA), and blank control group (SMMC-7721 cells did not received any treatment), and the expressions of FOXQ1 mRNA and its protein in SMMC-7721 cells were detected at 72 hours after transfection. ③ SMMC-7721 cells were divided into interference group, negative control group, blank control group, interference+oxaliplatin group, negative control+oxaliplatin group, and blank control+oxaliplatin group, apoptosis rates and viability of SMMC-7721 cells were detected at 48 hours after transfection. Results ① The expressions of FOXQ1 mRNA and its protein in SMMC-7721 cells of the FOXQ1-shRNA-1 group were both lower than those of the FOXQ1-shRNA-2 group and FOXQ1-shRNA-3 group (P<0.05), so the FOXQ1-shRNA-1 was the best lentiviral vector. ② Compared with the negative control group and the blank control group, the expressions of FOXQ1 mRNA and its protein of the interference group were both lower (P<0.05), but there was no significant difference between the negative control group and the blank control group (P>0.05). ③ Whether added oxaliplatin or not, compared with the negative control group and the blank control group, the apoptosis rates of the interference group were higher (P<0.05), but the viability of the interference group was lower (P<0.05), and there was no significant difference between the negative control group and the blank control group under the same condition (P>0.05). The apoptosis rates of groups (including the interference group, the negative control group, and the blank control group) which added oxaliplatin were higher than those groups didn’t add oxaliplatin (P<0.05), but viability of groups (including the interference group, the negative control group, and the blank control group) which added oxaliplatin was lower than those groups didn’t add oxaliplatin (P<0.05). Conclusion Down-regulation of expression of FOXQ1 by shRNA in hepatocellular carcinoma cell line SMMC-7721 can effectively induce apoptosis and increase sensitivity of SMMC-7721 cells to oxaliplatin.

Citation： DENG Dawei, WU Bin, YAN Shu, ZHANG Guangnian, LAN Chuan, YI Pengsheng, ZENG Lijuan, LI Jianshui. Enhanced sensitivity of hepatocellular carcinoma cell line SMMC-7721 to oxaliplatin by silencing forkhead box Q1 gene with RNA interference technology. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2018, 25(3): 289-295. doi: 10.7507/1007-9424.201708067 Copy

1.	Zhu Q, Li N, Zeng X, et al. Hepatocellular carcinoma in a large medical center of China over a 10-year period: evolving therapeutic option and improving survival. Oncotarget, 2015, 6(6): 4440-4450.
2.	Yang P, Markowitz GJ, Wang XF. The hepatitis B virus-associated tumor microenvironment in hepatocellular carcinoma. Natl Sci Rev, 2014, 1(3): 396-412.
3.	Zhang L, Ge C, Zhao F, et al. NRBP2 Overexpression Increases the Chemosensitivity of Hepatocellular Carcinoma Cells via Akt Signaling. Cancer Res, 2016, 76(23): 7059-7071.
4.	Katoh M, Igarashi M, Fukuda H, et al. Cancer genetics and genomics of human FOX family genes. Cancer Lett, 2013, 328(2): 198-206.
5.	Huang W, Chen Z, Shang X, et al. Sox12, a direct target of FoxQ1, promotes hepatocellular carcinoma metastasis through up-regulating Twist1 and FGFBP1. Hepatology, 2015, 61(6): 1920-1933.
6.	邓大炜, 孔宪炳, 王平, 等. FOXQ1 在肝癌中的临床意义及其对 SMMC-7721 细胞体外血管形成的影响. 中国生物化学与分子生物学报, 2015, 31(4): 422-428.
7.	李建水, 邓大炜, 曾丽娟. FOXQ1 促进肝癌细胞系 SMMC-7721 细胞的增殖. 中国生物化学与分子生物学报, 2016, 32(4): 446-451.
8.	王城, 吴斌, 严舒, 等. 沉默 FOXQ1 基因抑制肝细胞癌 SMMC-7721 细胞迁移侵袭能力. 中国肿瘤生物治疗杂志, 2017, 24(1): 48-52.
9.	段峰, 王茂强, 刘凤永, 等. 肝动脉化疗栓塞联合索拉非尼治疗肝细胞癌合并肺转移的临床观察. 中华肿瘤杂志, 2009, 31(9):716-718.
10.	Varga M, Valsamis A, Matia I, et al. Transarterial chemoembolization in hepatocellular carcinoma. Rozhl Chir, 2009, 88(8): 434-438.
11.	Asghar U, Meyer T. Are there opportunities for chemotherapy in the treatment of hepatocellular cancer? J Hepatol, 2012, 56(3): 686-695.
12.	Louafi S, Boige V, Ducreux M, et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase II study. Cancer, 2007, 109(7): 1384-1390.
13.	Kim HY, Park JW. Clinical trials of combined molecular targeted therapy and locoregional therapy in hepatocellular carcinoma: past, present, and future. Liver Cancer, 2014, 3(1): 9-17.
14.	Hsu CH, Shen YC, Shao YY, et al. Sorafenib in advanced hepatocellular carcinoma: current status and future perspectives. J Hepatocell Carcinoma, 2014, 1: 85-99.
15.	Kim DY. Can metronomic chemotherapy be an alternative to sorafenib in advanced hepatocellular carcinoma? Clin Mol Hepatol, 2017, 23(2): 123-124.
16.	Becker G, Soezgen T, Olschewski M, et al. Combined TACE and PEI for palliative treatment of unresectable hepatocellular carcinoma. World J Gastroenterol, 2005, 11(39): 6104-6109.
17.	Banfi A, Podestà M, Fazzuoli L, et al. High-dose chemotherapy shows a dose-dependent toxicity to bone marrow osteoprogenitors: a mechanism for post-bone marrow transplantation osteopenia. Cancer, 2001, 92(9): 2419-2428.
18.	Kato J, Kuwabara Y, Mitani M, et al. Expression of survivin in esophageal cancer: correlation with the prognosis and response to chemotherapy. Int J Cancer, 2001, 95(2): 92-95.
19.	Nielsen K, Scheffer HJ, Volders JH, et al. Radiofrequency ablation to improve survival after conversion chemotherapy for colorectal liver metastases. World J Surg, 2016, 40(8): 1951-1958.
20.	Xia L, Huang W, Tian D, et al. Forkhead box Q1 promotes hepatocellular carcinoma metastasis by transactivating ZEB2 and VersicanV1 expression. Hepatology, 2014, 59(3): 958-973.
21.	Peng X, Luo Z, Kang Q, et al. FOXQ1 mediates the crosstalk between TGF-β and Wnt signaling pathways in the progression of colorectal cancer. Cancer Biol Ther, 2015, 16(7): 1099-1109.
22.	Yonemori K, Seki N, Idichi T, et al. The microRNA expression signature of pancreatic ductal adenocarcinoma by RNA sequencing: anti-tumour functions of the microRNA-216 cluster. Oncotarget, 2017, 8(41): 70097-70115.
23.	Bao B, Azmi AS, Aboukameel A, et al. Pancreatic cancer stem-like cells display aggressive behavior mediated via activation of FoxQ1. J Biol Chem, 2014, 289(21): 14520-14533.
24.	Kaneda H, Arao T, Tanaka K, et al. FOXQ1 is overexpressed in colorectal cancer and enhances tumorigenicity and tumor growth. Cancer Res, 2010, 70(5): 2053-2063.

1. Zhu Q, Li N, Zeng X, et al. Hepatocellular carcinoma in a large medical center of China over a 10-year period: evolving therapeutic option and improving survival. Oncotarget, 2015, 6(6): 4440-4450.
2. Yang P, Markowitz GJ, Wang XF. The hepatitis B virus-associated tumor microenvironment in hepatocellular carcinoma. Natl Sci Rev, 2014, 1(3): 396-412.
3. Zhang L, Ge C, Zhao F, et al. NRBP2 Overexpression Increases the Chemosensitivity of Hepatocellular Carcinoma Cells via Akt Signaling. Cancer Res, 2016, 76(23): 7059-7071.
4. Katoh M, Igarashi M, Fukuda H, et al. Cancer genetics and genomics of human FOX family genes. Cancer Lett, 2013, 328(2): 198-206.
5. Huang W, Chen Z, Shang X, et al. Sox12, a direct target of FoxQ1, promotes hepatocellular carcinoma metastasis through up-regulating Twist1 and FGFBP1. Hepatology, 2015, 61(6): 1920-1933.
6. 邓大炜, 孔宪炳, 王平, 等. FOXQ1 在肝癌中的临床意义及其对 SMMC-7721 细胞体外血管形成的影响. 中国生物化学与分子生物学报, 2015, 31(4): 422-428.
7. 李建水, 邓大炜, 曾丽娟. FOXQ1 促进肝癌细胞系 SMMC-7721 细胞的增殖. 中国生物化学与分子生物学报, 2016, 32(4): 446-451.
8. 王城, 吴斌, 严舒, 等. 沉默 FOXQ1 基因抑制肝细胞癌 SMMC-7721 细胞迁移侵袭能力. 中国肿瘤生物治疗杂志, 2017, 24(1): 48-52.
9. 段峰, 王茂强, 刘凤永, 等. 肝动脉化疗栓塞联合索拉非尼治疗肝细胞癌合并肺转移的临床观察. 中华肿瘤杂志, 2009, 31(9):716-718.
10. Varga M, Valsamis A, Matia I, et al. Transarterial chemoembolization in hepatocellular carcinoma. Rozhl Chir, 2009, 88(8): 434-438.
11. Asghar U, Meyer T. Are there opportunities for chemotherapy in the treatment of hepatocellular cancer? J Hepatol, 2012, 56(3): 686-695.
12. Louafi S, Boige V, Ducreux M, et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase II study. Cancer, 2007, 109(7): 1384-1390.
13. Kim HY, Park JW. Clinical trials of combined molecular targeted therapy and locoregional therapy in hepatocellular carcinoma: past, present, and future. Liver Cancer, 2014, 3(1): 9-17.
14. Hsu CH, Shen YC, Shao YY, et al. Sorafenib in advanced hepatocellular carcinoma: current status and future perspectives. J Hepatocell Carcinoma, 2014, 1: 85-99.
15. Kim DY. Can metronomic chemotherapy be an alternative to sorafenib in advanced hepatocellular carcinoma? Clin Mol Hepatol, 2017, 23(2): 123-124.
16. Becker G, Soezgen T, Olschewski M, et al. Combined TACE and PEI for palliative treatment of unresectable hepatocellular carcinoma. World J Gastroenterol, 2005, 11(39): 6104-6109.
17. Banfi A, Podestà M, Fazzuoli L, et al. High-dose chemotherapy shows a dose-dependent toxicity to bone marrow osteoprogenitors: a mechanism for post-bone marrow transplantation osteopenia. Cancer, 2001, 92(9): 2419-2428.
18. Kato J, Kuwabara Y, Mitani M, et al. Expression of survivin in esophageal cancer: correlation with the prognosis and response to chemotherapy. Int J Cancer, 2001, 95(2): 92-95.
19. Nielsen K, Scheffer HJ, Volders JH, et al. Radiofrequency ablation to improve survival after conversion chemotherapy for colorectal liver metastases. World J Surg, 2016, 40(8): 1951-1958.
20. Xia L, Huang W, Tian D, et al. Forkhead box Q1 promotes hepatocellular carcinoma metastasis by transactivating ZEB2 and VersicanV1 expression. Hepatology, 2014, 59(3): 958-973.
21. Peng X, Luo Z, Kang Q, et al. FOXQ1 mediates the crosstalk between TGF-β and Wnt signaling pathways in the progression of colorectal cancer. Cancer Biol Ther, 2015, 16(7): 1099-1109.
22. Yonemori K, Seki N, Idichi T, et al. The microRNA expression signature of pancreatic ductal adenocarcinoma by RNA sequencing: anti-tumour functions of the microRNA-216 cluster. Oncotarget, 2017, 8(41): 70097-70115.
23. Bao B, Azmi AS, Aboukameel A, et al. Pancreatic cancer stem-like cells display aggressive behavior mediated via activation of FoxQ1. J Biol Chem, 2014, 289(21): 14520-14533.
24. Kaneda H, Arao T, Tanaka K, et al. FOXQ1 is overexpressed in colorectal cancer and enhances tumorigenicity and tumor growth. Cancer Res, 2010, 70(5): 2053-2063.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Enhanced sensitivity of hepatocellular carcinoma cell line SMMC-7721 to oxaliplatin by silencing forkhead box Q1 gene with RNA interference technology

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