The fibroblast growth factor receptor 2‑mediated extracellular signal-regulated kinase 1/2 signaling pathway plays is important in regulating excision repair cross‑complementary gene 1 expression in hepatocellular carcinoma

Chen,Gang; Qiu,Hong; Ke,Shandong; Hu,Shaoming; Yu,Shiying; Zou,Shengquan

doi:10.3892/br.2013.96

July-August 2013 Volume 1 Issue 4

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

July-August 2013 Volume 1 Issue 4

Full Size Image

Article

The fibroblast growth factor receptor 2‑mediated extracellular signal-regulated kinase 1/2 signaling pathway plays is important in regulating excision repair cross‑complementary gene 1 expression in hepatocellular carcinoma

Authors:
- Gang Chen
- Hong Qiu
- Shandong Ke
- Shaoming Hu
- Shiying Yu
- Shengquan Zou
View Affiliations / Copyright

Affiliations: Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
Pages: 604-608
|
Published online on: April 19, 2013

https://doi.org/10.3892/br.2013.96
Expand metrics +

Abstract

Excision repair cross‑complementary gene 1 (ERCC1) is a downstream regulatory target of fibroblast growth factor receptor 2 (FGFR2); however, the mechanism of its action has not been elucidated. The cascades downstream of FGFR2 include the PKC, Ras̸Raf̸MEK̸ERK, JAK̸STAT and PI3K pathways. ERCC1 is considered to be a closely related downstream target gene of extracellular signal‑regulated kinase (ERK)1/2, since ERCC1 mRNA and protein levels may be inhibited by the ERK inhibitor U0126. It was hypothesized that FGFR2, which specifically binds with fibroblast growth factor 7 (FGF7), may regulate ERCC1 gene expression through the ERK signaling pathway. The aim of the present study was to explore the association between the regulatory effect of FGFR2 on ERCC1 gene expression and the p‑ERK1/2 signaling pathway in a drug‑resistant hepatocellular carcinoma (HCC) cell line. The drug‑resistant cell line HepG2/OXA and its parental cell line HepG2 were transfected with Bek shRNA in the logarithmic growth phase. Transfected and untransfected HepG2 and HepG2/OXA cells were then stimulated with FGF7 and changes in the protein expression of FGFR2, p‑ERK1/2 and ERCC1 was detected with western blot analysis. Following transfection, HepG2̸T and HepG2̸OXA̸T cells were observed to grow stably in a screening medium containing puromycin. The western blot analysis demonstrated a significant decrease in the protein expressions of FGFR2, p‑ERK1/2 and ERCC1 in HepG2̸T and HepG2/OXA/T cells as compared to untransfected cells. Expression of FGFR2, p‑ERK1/2 and ERCC1 in HepG2/OXA cells was significantly increased compared to the parental HepG2 cells. Following stimulation with FGF7, the expression of FGFR2, p‑ERK1/2 and ERCC1 was increased, with significant differences between HepG2 and HepG2/OXA cells in the expression of p‑ERK1̸2 and ERCC1. No differences were detected in the protein levels following Bek shRNA transfection in HepG2̸T and HepG2/OXA/T cells. In conclusion, the FGFR2‑mediated ERK1/2 signaling pathway in HCC cells plays an important role in the regulation of ERCC1 expression.

View Figures

View References

1.	Llovcet JM, Burroughs A and Bruix J: Hepatocellular carcinoma. Lancet. 362:1907–1917. 2003. View Article : Google Scholar
2.	El-Serag HB and Rudolph KL: Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 132:2557–2576. 2007. View Article : Google Scholar : PubMed/NCBI
3.	El-Serag HB, Marrero JA, Rudolph L and Reddy KR: Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology. 134:1752–1763. 2008. View Article : Google Scholar : PubMed/NCBI
4.	Katoh M: Cancer genomics and genetics of FGFR2 (Review). Int J Oncol. 33:233–237. 2008.PubMed/NCBI
5.	Fautrel A, Andrieux L, Musso O, Boudjema K, Guillouzo A and Langouët S: Overexpression of the two nucleotide excision repair genes ERCC1 and XPC in human hepatocellular carcinoma. J Hepatol. 43:288–293. 2005. View Article : Google Scholar : PubMed/NCBI
6.	Ueda S, Shirabe K, Morita K, Umeda K, Kayashima H, Uchiyama H, Soejima Y, Taketomi A and Maehara Y: Evaluation of ERCC1 expression for cisplatin sensitivity in human hepatocellular carcinoma. Ann Surg Oncol. 18:1204–1211. 2011. View Article : Google Scholar : PubMed/NCBI
7.	Wu Q, Beland FA, Chang CW and Fang JL: XPC is essential for nucleotide excision repair of zidovudine-induced DNA damage in human hepatoma cells. Toxicol Appl Pharmacol. 251:155–162. 2011. View Article : Google Scholar : PubMed/NCBI
8.	Gauglhofer C, Sagmeister S, Schrottmaier W, et al: Up-regulation of the fibroblast growth factor 8 subfamily in human hepatocellular carcinoma for cell survival and neoangiogenesis. Hepatology. 53:854–864. 2011. View Article : Google Scholar : PubMed/NCBI
9.	Harimoto N, Taguchi K, Shirabe K, Adachi E, Sakaguchi Y, Toh Y, Okamura T, Kayashima H, Taketomi A and Maehara Y: The significance of fibroblast growth factor receptor 2 expression in differentiation of hepatocellular carcinoma. Oncology. 78:361–368. 2010. View Article : Google Scholar : PubMed/NCBI
10.	Bai A, Meetze K, Vo NY, et al: GP369, an FGFR2-IIIb-specific antibody, exhibits potent antitumor activity against human cancers driven by activated FGFR2 signaling. Cancer Res. 70:7630–7639. 2010. View Article : Google Scholar : PubMed/NCBI
11.	Qiu H, Yashiro M, Zhang X, Miwa A and Hirakawa K: A FGFR2 inhibitor, Ki23057, enhances the chemosensitivity of drug-resistant gastric cancer cells. Cancer Lett. 307:47–52. 2011. View Article : Google Scholar : PubMed/NCBI
12.	Katoh M and Katoh M: FGF signaling network in the gastrointestinal tract (Review). Int J Oncol. 29:163–168. 2006.PubMed/NCBI
13.	Ko JC, Su YJ, Lin ST, Jhan JY, Ciou SC, Cheng CM and Lin YW: Suppression of ERCC1 and Rad51 expression through ERK1/2 inactivation is essential in emodin-mediated cytotoxicity in human non-small cell lung cancer cells. Biochem Pharmacol. 79:655–664. 2010. View Article : Google Scholar : PubMed/NCBI
14.	Ko JC, Tsai MS, Kuo YH, et al: Modulation of Rad51, ERCC1, and thymidine phosphorylase by emodin result in synergistic cytotoxic effect in combination with capecitabine. Biochem Pharmacol. 81:680–690. 2011. View Article : Google Scholar : PubMed/NCBI
15.	Youn CK, Kim MH, Cho HJ, Kim HB, Chang IY, Chung MH and You HJ: Oncogenic H-Ras up-regulates expression of ERCC1 to protect cells from platinum-based anticancer agents. Cancer Res. 64:4849–4857. 2004. View Article : Google Scholar : PubMed/NCBI
16.	Wilson LA, Yamamoto H and Singh G: Role of the transcription factor Ets-1 in cisplatin resistance. Mol Cancer Ther. 3:823–832. 2004.PubMed/NCBI
17.	Logan SK, Garabedian MJ, Campbell CE and Werb Z: Synergistic transcriptional activation of the tissue inhibitor of metalloproteinases-1 promoter via functional interaction of AP-1 and Ets-1 transcription factors. J Biol Chem. 271:774–782. 1996. View Article : Google Scholar : PubMed/NCBI
18.	Andrieux LO, Fautrel A, Bessard A, Guillouzo A, Baffet G and Langouët S: GATA-1 is essential in EGF-mediated induction of nucleotide excision repair activity and ERCC1 expression through ERK2 in human hepatoma cells. Cancer Res. 67:2114–2123. 2007. View Article : Google Scholar : PubMed/NCBI