Add like
Add dislike
Add to saved papers

IL-6/STAT3 Signaling Contributes to Sorafenib Resistance in Hepatocellular Carcinoma Through Targeting Cancer Stem Cells.

Background: Sorafenib is the standard first-line treatment for advanced hepatocellular carcinoma (HCC), even though acquired resistance to sorafenib has been found in many HCC patients, resulting in poor prognosis. Accumulating evidence demonstrates that liver cancer stem cells (LCSCs) contribute to sorafenib resistance in HCC. The inflammatory factor interleukin 6 (IL-6) plays a role in sorafenib resistance in HCC. However, the mechanism by which IL-6 in LCSCs is involved in the process of HCC sorafenib resistance remains elusive.

Methods: In this study, the sorafenib-resistant cell line PLC/PRF/5-R was generated by the concentration gradient method, and cell viability was determined by the CCK-8 assay. LCSCs were isolated from the PLC/PRF/5-R cell line by flow cytometry, and tumorigenesis was confirmed in nude mice. Blockade of IL-6 cells was achieved by lentiviral-mediated interference. The protein levels of stem cell markers (EpCAM, CD44), stemness markers (Oct3/4, β-catenin), and hepatocyte differentiation markers (glucose-6-phosphate, AFP) were measured by Western blotting analysis. Finally, a xenograft model was used to evaluate the function of IL-6 in the sorafenib resistance of HCC.

Results: The stable sorafenib-resistant HCC cell line PLC/PRF/5-R was established and showed significant epithelial-mesenchymal transition (EMT) characteristics; the isolated resistant LCSCs from PLC/PRF/5-R were more tumorigenic than the control LCSCs. We showed that IL-6, IL-6R, STAT3 and GP130 expression were dramatically increased in resistant LCSCs compared to control LCSCs. Downregulation of IL-6 expression with short hairpin RNA (shRNA) restored sorafenib sensitivity in resistant LCSCs, suggesting the critical roles of IL-6/STAT3 in inducing sorafenib resistance. Furthermore, a xenograft tumor model showed that IL-6 downregulation improved the antitumor effect of sorafenib.

Conclusion: LCSCs play an important role in sorafenib-resistant HCC, and inhibition of the IL-6/STAT3 signaling pathway improves the antitumor effects of sorafenib against HCC in vitro and in vivo. These findings demonstrate that IL-6 in LCSCs may function as a novel target for combating sorafenib resistance in HCC.

Full text links

We have located links that may give you full text access.
Can't access the paper?
Try logging in through your university/institutional subscription. For a smoother one-click institutional access experience, please use our mobile app.

For the best experience, use the Read mobile app

Mobile app image

Get seemless 1-tap access through your institution/university

For the best experience, use the Read mobile app

All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

By using this service, you agree to our terms of use and privacy policy.

Your Privacy Choices Toggle icon

You can now claim free CME credits for this literature searchClaim now

Get seemless 1-tap access through your institution/university

For the best experience, use the Read mobile app