title: Peritumoral Cbl is a strong independent prognostic marker after curative resection of hepatocellular carcinoma.
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 (Cbl) 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 Cbl 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.
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shangai, China.
authors.forename: Ju-Bo
authors.initials: JB
authors.lastname: Zhang
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shangai, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shangai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shangai, China.
authors.forename: Zhen-Hai
authors.initials: ZH
authors.lastname: Lin
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shangai, China.
authors.forename: Xiao-Qiang
authors.initials: XQ
authors.lastname: Li
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shangai, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Guo
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shangai, China.
authors.forename: Hui-Chuan
authors.initials: HC
authors.lastname: Sun
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China.|Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shangai, China.
authors.forename: Qing-Hai
authors.initials: QH
authors.lastname: Ye
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000378:metabolism* / Q000601:surgery; D015331:Cohort Studies; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D017063:Outcome Assessment, Health Care; D011379:Prognosis; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D016019:Survival Analysis; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors
keywords: casitas B-lineage lymphoma; epidermal growth factor receptor; hepatocellular carcinoma; peritumoral microenvironment; prognosis