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Functional Genomics Identifies Hepatitis-Induced STAT3-TYRO3-STAT3 Signaling as a Potential Therapeutic Target of
Chia-Liang Tsai1,2, Jeng-Shou Chang1, Ming-Chin Yu3
1Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
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.
Insights
Hepatitis promotes liver cancer (HCC) by activating TYRO3 receptor tyrosine kinase (RTK) signaling. Targeting TYRO3 may offer a new strategy for treating hepatitis-related HCC.
Area of Science:
- Hepatology
- Oncology
- Molecular Biology
Background:
- Hepatitis is a known risk factor for hepatocellular carcinoma (HCC) development and recurrence.
- Receptor tyrosine kinases (RTKs) are crucial in various cancer progressions.
- The specific roles of RTKs in hepatitis-associated HCC remain largely unexplored.
Purpose of the Study:
- To investigate the involvement of RTKs in the pathogenesis of hepatitis-related HCC.
- To identify specific RTKs that play critical roles in the development of liver cancer linked to hepatitis.
Main Methods:
- Conducted loss-of-function screening to identify key RTKs in HCC development.
- Utilized in vitro and in vivo models to study RTK functions.
- Analyzed gene expression, signaling pathways (IL-6/IL6R-STAT3, SRC), and therapeutic interventions.
Main Results:
- Multiple RTKs were coexpressed and implicated in HCC growth.
- TYRO3 was identified as a key RTK promoting tumor growth, associated with hepatitis activity and poor prognosis.
- Hepatitis induced Tyro3 expression via IL-6/IL6R-STAT3 signaling, and apoptotic cells enhanced TYRO3 activation.
- TYRO3 activation led to SRC and STAT3 signaling, synergistically promoting HCC in mice.
- TYRO3 silencing or inhibition reduced HCC xenograft growth.
Conclusions:
- RTKs are significantly involved in hepatitis-associated HCC.
- TYRO3 plays a critical role in promoting HCC growth through a "TYRO3-STAT3-TYRO3" signaling loop.
- TYRO3 represents a potential biomarker and therapeutic target for HCC with high hepatitis activity.
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