Axl Expression Stratifies Patients with Poor Prognosis after Hepatectomy for Hepatocellular Carcinoma

Jian Liu; Kui Wang; Zhenlin Yan; Yong Xia; Jun Li; Lehua Shi; Qifei Zou; Xuying Wan; Binghua Jiao; Hongyang Wang; Mengchao Wu; Yongjie Zhang; Feng Shen

doi:10.1371/journal.pone.0154767

Axl Expression Stratifies Patients with Poor Prognosis after Hepatectomy for Hepatocellular Carcinoma

PLoS One. 2016 May 16;11(5):e0154767. doi: 10.1371/journal.pone.0154767. eCollection 2016.

Authors

Jian Liu¹, Kui Wang¹, Zhenlin Yan¹, Yong Xia¹, Jun Li¹, Lehua Shi¹, Qifei Zou¹, Xuying Wan², Binghua Jiao³, Hongyang Wang⁴, Mengchao Wu^{1

4}, Yongjie Zhang⁵, Feng Shen¹

Affiliations

¹ Department of Hepatic Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
² Department of Clinical Database, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
³ Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China.
⁴ National Scientific Center for Liver Cancer, Shanghai, China.
⁵ Department of Biliary Surgery, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.

Abstract

Background: Axl is a receptor tyrosine kinase which plays an important role in multiple human malignancies.

Design: The Axl expression was examined in several hepatocellular carcinoma(HCC) cell lines, paired tumor and nontumorous samples. Then, we examined cell growth curve, cell apoptosis and cell migration in SMMC-7721 cells over-expressed with Axl or siRNA against Axl, respectively. Finally, the prognostic value of Axl was investigated in a prospective cohort of 246 consecutive HCC patients undergoing curative hepatoectomy.

Results: We found Axl was positive in 22% of examined tumor tissues and all four cell lines. Over-expressing Axl in SMMC-7721 cells accelerated cell growth, cell migration and inhibited cell apoptosis, while knock-down of Axl exerted opposite effect. Axl expression was closely associated with serum AFP, multiple tumors, absence of encapsulation, microvascular invasion, and advanced BCLC or TNM stage. Patients with positive Axl staining had a higher 5-year recurrence rate (92% vs. 71%, P<0.001) and a lower 5-year survival rate (9% vs. 48%, P<0.001) than those with negative staining. The multivariate analyses showed that Axl expression was an independent factor for both tumor recurrence (HR: 1.725; 95% CI: 1.219-2.441) and survival (1.847; 1.291-2.642).

Conclusion: Axl expression suggests more aggressive tumor invasiveness and predicts worse prognosis for HCC patients undergoing resection.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Axl Receptor Tyrosine Kinase
Biomarkers, Tumor
Carcinoma, Hepatocellular / diagnosis
Carcinoma, Hepatocellular / genetics*
Carcinoma, Hepatocellular / mortality*
Carcinoma, Hepatocellular / surgery
Cell Line, Tumor
Female
Follow-Up Studies
Gene Expression*
Gene Knockdown Techniques
Hepatectomy
Humans
Liver Neoplasms / genetics*
Liver Neoplasms / mortality*
Liver Neoplasms / surgery
Male
Middle Aged
Neoplasm Grading
Neoplasm Staging
Prognosis
Proto-Oncogene Proteins / genetics*
RNA Interference
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptor Protein-Tyrosine Kinases / genetics*
Tumor Burden
Young Adult

Substances

Biomarkers, Tumor
Proto-Oncogene Proteins
RNA, Messenger
Receptor Protein-Tyrosine Kinases
Axl Receptor Tyrosine Kinase
AXL protein, human

Grants and funding

This work was supported by grants from National Natural Science Foundation of China (grant number 81071867 to KW; grant number 30772141 to SF; grant number 30921006 to HYW); a grant from the State Key Project on Infectious Diseases of China (grant number 2012ZX10002 -011,016 to FS); and a grant of Shanghai Hospital Development Program (grant number SHDC12010121 to FS).