Expression of variant isoforms of the tyrosine kinase SYK determines the prognosis of hepatocellular carcinoma.
The spleen tyrosine kinase (SYK) has been reported as a novel biomarker for human hepatocellular carcinoma, but the functional contributions of its two isoforms SYK(L) and SYK(S) are undefined. In this study, we investigated their biologic functions and possible prognostic values in hepatocellular carcinoma. SYK(L) was downregulated in 38% of human specimens of hepatocellular carcinoma examined, whereas SYK(S) was detectable in 40% of these specimens but not in normal liver tissue samples without cirrhosis. SYK(S) expression correlated with pathologic parameters characteristic of tumor metastasis, including multiple tumors (P = 0.003) and vascular invasion (P = 0.001). Further, SYK(S) was specifically associated with epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma specimens. Functional studies showed that SYK(S) promoted tumor growth, suppressed apoptosis, and induced EMT through the extracellular signal-regulated kinase pathway, countering the opposite effects of SYK(L). Patients with SYK(L(+)/S(-)) tumors exhibited longer overall survival and time to recurrence than those with SYK(L(-)/S(-)) or SYK(L(+)/S(+)) tumors (P < 0.001). Taken together, our findings showed that SYK(S) enhances invasion, whereas SYK(L) inhibits metastasis in hepatocellular carcinoma. We suggest that SYK(L) downregulation or SYK(S) elevation are strong predictors of poor survival in patients with hepatocellular carcinoma, indicative of a need for aggressive therapeutic intervention.
Authors' Affiliations: State Key Laboratory of Oncology in South China; Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center; Department of Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and Division of Pharmacy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
Jian
J
Hong
Yunfei
Y
Yuan
Jianping
J
Wang
Yadi
Y
Liao
Ruhai
R
Zou
Chuanlong
C
Zhu
Binkui
B
Li
Yi
Y
Liang
Pinzhu
P
Huang
Zongwei
Z
Wang
Wenyu
W
Lin
Yixin
Y
Zeng
Jia Le
JL
Dai
Raymond T
RT
Chung
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000401:mortality / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000556:secondary; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D000072377:Syk Kinase
D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse