Oncotarget

Research Papers:

Peritumoral Cbl is a strong independent prognostic marker after curative resection of hepatocellular carcinoma

Ju-Bo Zhang _, Bo Zhang, Lei Guo, Zhen-Hai Lin, Xiao-Qiang Li, Kun Guo, Hui-Chuan Sun and Qing-Hai Ye

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Oncotarget. 2015; 6:40223-40234. https://doi.org/10.18632/oncotarget.5540

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Abstract

Ju-Bo Zhang1,2, Bo Zhang1,2, Lei-Guo1,2, Zhen-Hai Lin1,2, Xiao-Qiang Li1,2, Kun Guo1,2, Hui-Chuan Sun1,2, Qing-Hai Ye1,2

1Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China

2Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shangai, China

Correspondence to:

Qing-Hai Ye, e-mail: ye.qinghai@zs-hospital.sh.cn

Hui-Chuan Sun, e-mail: sun.huichuan@zs-hospital.sh.cn

Keywords: hepatocellular carcinoma, casitas B-lineage lymphoma, peritumoral microenvironment, epidermal growth factor receptor, prognosis

Received: April 26, 2015     Accepted: October 02, 2015     Published: October 13, 2015

ABSTRACT

Growing evidences support the concept that peritumoral microenvironment gene expression is an important element for physicians to make an accurate prognosis. Nonetheless, the correlation between peritumoral ubiquitin ligases and the hepatocellular carcinoma (HCC) survival remains unclear till this present. The expression of intratumoral and peritumoral Casitas B-lineage Lymphoma (cb1) and epidermal growth factor receptor (EGFR) in hepatocellular carcinomas (HCCs) followed by curative resection was assessed by tissue microarray-based immune-histochemistry in two independent cohorts (n = 352). Their respective prognostic values and other clinicopathologic factors were then evaluated. The peritumoral cbl density, much higher than that in intratumoral tissue, was an independent prognostic factor for overall survival (P < 0.001) and time to recurrence (P < 0.001) of HCCs after curative resection. The hazard ratio were 1.587 and 1.689, respectively. However, there was no correlation between intratumoral Cbl and prognosis. The peritumoral Cbl was also associated with prognosis even in HCC subgroups with small tumor size, negative AFP, without microvascular invasion and negative HBeAg. After a thorough analysis pertaining to the key role of Cb1 on ubiquitination and degradation of activated receptor tyrosine kinases, we eventually discovered the negative correlation between peritumoral Cbl and EGFR (P = 0.015). Furthermore, the combination of peritumoral Cbl and EGFR serves as a much stronger indicator to make an accurate prognosis, especially during early recurrence (P < 0.001). These findings suggest that low expression of peritumoral Cbl and EGFR were positively associated with tumor size, microvascular invasion and patients survival after hepatectomy, highlighting the key role of peritumoral liver milieu in HCC progression.


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