Overexpression of semaphorin 3A promotes tumor progression and predicts poor prognosis in hepatocellular carcinoma after curative resection
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Zhi-Qiang Hu1,*, Shao-Lai Zhou1,*, Zheng-Jun Zhou1, Chu-Bin Luo1, Er-Bao Chen1, Hao Zhan1, Peng-Cheng Wang1, Zhi Dai1, Jian Zhou1, Jia Fan1, Xiao-Wu Huang1
1Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai 200032, China
*These authors have contributed equally to this work
Xiao-Wu Huang, email: [email protected]
Keywords: hepatocellular carcinoma, semaphorin 3A, tumor-associated macrophages, prognosis
Received: December 16, 2015 Accepted: May 12, 2016 Published: June 16, 2016
The semaphorins were originally identified as having roles as guidance cues during neural development. Class 3 semaphorins are involved in cancer progression. However, the roles of class 3 semaphorins in hepatocellular carcinoma (HCC) are unknown. We examined the expression levels of class 3 semaphorins in HCC cell lines with different metastatic potential and in carcinoma tissue samples. The results indicated that Semaphorin 3A expression was up-regulated in metastatic cell lines and in samples from patients with tumor recurrence. Cell functional studies revealed that Semaphorin 3A promoted HCC cell proliferation, migration, and invasion. Animal studies indicated that Semaphorin 3A overexpression enhanced tumor growth and lung metastasis. Semaphorin 3A also acted as a chemoattractant involved in direct recruitment of macrophages in vitro, and facilitated tumor-associated macrophage (TAM) infiltration in vivo. Multivariate analysis revealed that Semaphorin 3A expression alone, or combined with the number of TAMs, can be an independent predictor for overall survival time and time to recurrence. Overall, the results suggested that Semaphorin 3A increased TAM infiltration and promoted HCC progression. Semaphorin 3A expression alone, or combined with the number of TAMs, is a new prognostic factor and potential target for the treatment of HCC.
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