Elevated Src expression associated with hepatocellular carcinoma metastasis in northern Chinese patients

Zhao,Ran; Wu,Yiqi; Wang,Tianzhen; Zhang,Yuhua; Kong,Dan; Zhang,Lei; Li,Xiaobo; Wang,Guangyu; Jin,Yinji; Jin,Xiaoming; Zhang,Fengmin

doi:10.3892/ol.2015.3706

Elevated Src expression associated with hepatocellular carcinoma metastasis in northern Chinese patients

Authors:
- Ran Zhao
- Yiqi Wu
- Tianzhen Wang
- Yuhua Zhang
- Dan Kong
- Lei Zhang
- Xiaobo Li
- Guangyu Wang
- Yinji Jin
- Xiaoming Jin
- Fengmin Zhang
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Affiliations: Department of Pathology, Basic Medical Science College, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China, Department of Gynecology, Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China, Department of Oncology, Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China, Department of Microbiology, Basic Medical Science College, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
Published online on: September 16, 2015 https://doi.org/10.3892/ol.2015.3706
Pages: 3026-3034

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Abstract

Src, a non-receptor type of tyrosine, was recently reported to modulate multiple signaling pathways in human tumors. Therefore, the present study aimed to determine the expression and distribution of Src on hepatocellular carcinoma (HCC). The expressions of total Src (t‑Src) and an active form of Src [phosphorylated (p‑) Y416Src] were analyzed in 52 northern Chinese patients with HCC using immunohistochemistry. The positive expression rates of t‑Src and p‑Y416Src in HCC tissue were 65.38 and 42.30%, respectively, which is significantly higher than that in adjacent non‑tumor tissue (30.76 and 13.46%; P<0.001 and P=0.010, respectively). The staining intensity of t‑Src and p‑Y416Src were also significantly higher in HCC tissues compared with adjacent normal tissues (P<0.001 and P=0.023, respectively). t‑Src expression was positively and significantly correlated with tumor stage (P=0.002), cellular differentiation (P=0.007), metastasis (P=0.030) and the expression level of CA19‑9 (P=0.016), while p‑Y416Src expression was only significantly correlated with tumor stage (P=0.010). The expression of t‑Src and p‑Y416Src were also investigated using immunocytochemistry in two HCC cell lines with different metastatic potentials (MHCC97‑L and HCCLM3) that are derived from a single HCC patient. Consistently, the expression of t‑Src and p‑Y416Src were stronger in the cells with higher metastatic potential compared with those exhibiting lower metastatic potential. Taken together, the current data indicate that Src expression is elevated and active in Chinese patients with HCC and that t‑Src may have a key role in promoting HCC metastasis.

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1	Farazi PA and Depinho RA: The genetic and environmental basis of hepatocellular carcinoma. Discov Med. 6:182–186. 2006.PubMed/NCBI
2	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistic, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar : PubMed/NCBI
3	He J, Gu D, Wu X, et al: Major causes of death among men and women in China. N Engl J Med. 353:1124–1134. 2005. View Article : Google Scholar : PubMed/NCBI
4	Hussain SA, Ferry DR, El-Gazzaz G, Mirza DF, James ND, McMaster P and Kerr DJ: Hepatocellular carcinoma. Ann Oncol. 12:161–172. 2001. View Article : Google Scholar : PubMed/NCBI
5	Shimizu I, Kohno N, Tamaki K, Shono M, Huang HW, He JH and Yao DF: Female hepatology: Favorable role of estrogen in chronic liver disease with hepatitis B virus infection. World J Gastroenterol. 13:4295–4305. 2007.PubMed/NCBI
6	Tang Z, Zhou X, Lin Z, Yang B, Ma Z, Ye S, Wu Z, Fan J, Liu Y, Liu K, et al: Surgical treatment of hepatocellular carcinoma and related basic research with special reference to recurrence and metastasis. Chin Med J (Engl). 112:887–891. 1999.PubMed/NCBI
7	Collett MS and Erikson RL: Protein kinase activity associated with the avian sarcoma virus src gene product. Proc Natl Acad Sci USA. 75:2021–2024. 1978. View Article : Google Scholar : PubMed/NCBI
8	Ingley E: Src family kinases: Regulation of their activities, levels and identification of new pathways. Biochim Biophys Acta. 56(65): 17842008.
9	Bolos V, Gasent JM, Lopez-Tarruella S and Grande E: The dual kinase complex FAK-Src as a promising therapeutic target in cancer. Onco Targets Ther. 3:83–97. 2010. View Article : Google Scholar : PubMed/NCBI
10	Frame MC: Src in cancer: Deregulation and consequences for cell behaviour. Biochim Biophys Acta. 1602:114–130. 2002.PubMed/NCBI
11	Yeatman TJ: A renaissance for SRC. Nat Rev Cancer. 4:470–480. 2004. View Article : Google Scholar : PubMed/NCBI
12	Chen J: Is Src the key to understanding metastasis and developing new treatments for colon cancer? Nat Clin Pract Gastroenterol Hepatol. 5:306–307. 2008. View Article : Google Scholar : PubMed/NCBI
13	Masaki T, Okada M, Shiratori Y, Rengifo W, Matsumoto K, Maeda S, Kato N, Kanai F, Komatsu Y, Nishioka M and Omata M: pp60c-src activation in hepatocellular carcinoma of human and LEC rats. Hepatology. 27:1257–1264. 1998. View Article : Google Scholar : PubMed/NCBI
14	Sun CK, Man K, Ng KT, Ho JW, Lim ZX, Cheng O, Lo CM, Poon RT and Fan ST: Proline-rich tyrosine kinase 2 (Pyk2) promotes proliferation and invasiveness of hepatocellular carcinoma cells through c-Src/ERK activation. Carcinogenesis. 29:2096–2105. 2008. View Article : Google Scholar : PubMed/NCBI
15	De Toni EN, Thieme SE, Herbst A, Behrens A, Stieber A, Jung A, Blum H, Göke H and Kolligs FT: OPG is regulated by beta-catenin and mediates resistance to TRAIL-induced apoptosis in colon cancer. Clin Cancer Res. 14:4713–4718. 2008. View Article : Google Scholar : PubMed/NCBI
16	Tian J, Tang ZY, Ye SL, Liu YK, Lin ZY, Chen J and Xue Q: New human hepatocellular carcinoma (HCC) cell line with highly metastatic potential (MHCC97) and its expressions of the factors associated with metastasis. Br J Cancer. 81:814–821. 1999. View Article : Google Scholar : PubMed/NCBI
17	Li Y, Tian B, Yang J, Zhao L, Wu X, Ye SL, Liu YK and Tang ZY: Stepwise metastatic human hepatocellular carcinoma cell line model system with multiple metastatic potentials establish through consecutive in vivo selection and studies on metastatic characteristics. J Cancer Res Clin Oncol. 130:460–468. 2004. View Article : Google Scholar : PubMed/NCBI
18	National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary cancers. Version 2. 2012.http://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdfAccessed. August 27–2015
19	Ryder SD: British Society of Gastroenterology: Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults. Gut. 52(Suppl 3): iii1–iii8. 2003.PubMed/NCBI
20	Greene FL, Page DL, Fleming ID, Fritz A, Balch CM and Haller DG: Liver Staging Form. AJCC Cancer Staging Manual (6th). (New York). Springer-Verlag. 1312002.
21	Wu Y, Wang T, Ye S, Zhao R, Bai X, Wu Y, Abe K and Jin X: Detection of hepatitis B virus DNA in paraffin-embedded intrahepatic and extrahepatic cholangiocarcinoma tissue in the northern Chinese population. Hum Pathol. 43:56–61. 2012. View Article : Google Scholar : PubMed/NCBI
22	Allred DC, Clark GM, Elledge R, Fuqua SA, Brown RW, Chamness GC, Osborne CK and McGuire WL: Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer. J Natl Cancer Inst. 85:200–206. 1993. View Article : Google Scholar : PubMed/NCBI
23	Lau GM, Lau GM, Yu GL, et al: Expression of Src and FAK in hepatocellular carcinoma and the effect of Src inhibitors on hepatocellular carcinoma in vitro. Dig Dis Sci. 54:1465–1474. 2009. View Article : Google Scholar : PubMed/NCBI
24	Morgan L, Nicholson RI and Hiscox S: SRC as a therapeutic target in breast cancer. Endocr Metab Immune Disord Drug Targets. 8:273–278. 2008. View Article : Google Scholar : PubMed/NCBI
25	Anbalagan M, Moroz K, Ali A, Carrier L, Glodowski S and Rowan BG: Subcellular localization of total and activated Src kinase in African American and Caucasian breast cancer. PLoS One. 7:e330172012. View Article : Google Scholar : PubMed/NCBI
26	Ito Y, Kawakatsu H, Takeda T, Sakon M, Nagano H, Sakai T, Miyoshi E, Noda K, Tsujimoto M, Wakasa K, et al: Activation of c-src gene product in hepatocellular carcinoma is highly correlated with the indices of early stage phenotype. J Hepatol. 35:68–73. 2001. View Article : Google Scholar : PubMed/NCBI
27	Chen ML, Chai CY, Yeh KT, Wang SN, Tsai CJ, Yeh YT and Yang SF: Crosstalk between activated and inactivated c-Src in hepatocellular carcinoma. Dis Markers. 30:325–333. 2011. View Article : Google Scholar : PubMed/NCBI
28	Hunter T: A tail of two src's: Mutatis mutandis. Cell. 49:1–4. 1987. View Article : Google Scholar : PubMed/NCBI
29	Roskoski R: Src protein-tyrosine kinase structure and regulation. Biochem Biophys Res Commun. 324:1155–1164. 2004. View Article : Google Scholar : PubMed/NCBI