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Functional Genomics Identifies Hepatitis-Induced STAT3-TYRO3-STAT3 Signaling as a Potential Therapeutic Target of Hepatoma.
Clinical Cancer Research ( IF 11.5 ) Pub Date : 2020-03-01 , DOI: 10.1158/1078-0432.ccr-18-3531 Chia-Liang Tsai,Jeng-Shou Chang,Ming-Chin Yu,Chern-Horng Lee,Tse-Ching Chen,Wen-Yu Chuang,Wei-Liang Kuo,Chen-Chun Lin,Shi-Ming Lin,Sen-Yung Hsieh
Clinical Cancer Research ( IF 11.5 ) Pub Date : 2020-03-01 , DOI: 10.1158/1078-0432.ccr-18-3531 Chia-Liang Tsai,Jeng-Shou Chang,Ming-Chin Yu,Chern-Horng Lee,Tse-Ching Chen,Wen-Yu Chuang,Wei-Liang Kuo,Chen-Chun Lin,Shi-Ming Lin,Sen-Yung Hsieh
PURPOSE
Hepatitis promotes the development and recurrence of hepatocellular carcinoma (HCC). Receptor tyrosine kinases (RTK) play critical roles in the development of many cancers. We explored the potential roles of RTKs in hepatitis-related liver cancers.
EXPERIMENTAL DESIGN
We conducted loss-of-function screening to elucidate the roles of RTKs in the development of HCC in vitro and in vivo.
RESULTS
Many RTKs were coexpressed in HCC and were involved in tumor development and growth. Of these, TYRO3 promoted tumor growth and was clinically associated with hepatitis activity and poor prognosis. In mice, chemical-induced hepatitis transcriptionally activated Tyro3 expression via IL-6/IL6R-STAT3 signaling. Moreover, hepatitis-associated apoptotic cells facilitated the presentation of GAS6, a TYRO3 ligand, to further activate TYRO3-mediated signaling. Furthermore, TYRO3 activation elicited intracellular SRC- and STAT3 signaling. In mice, hepatitis and Tyro3 synergistically promoted HCC development. Silencing TYRO3 expression or inhibiting its kinase activity suppressed xenograft HCC growth in nude mice.
CONCLUSIONS
Many RTKs are simultaneously involved in HCC development. Hepatitis exerts dual effects on the activation of TYRO3-mediated signaling in HCC cells, which further elicits the "TYRO3-STAT3-TYRO3" signaling loop to facilitate tumor growth. Our findings unveil a previously unrecognized link between RTKs and hepatitis-associated HCC and suggest TYRO3 as a marker and therapeutic target for the HCCs with higher hepatitis activity.
更新日期:2020-04-21