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Conference Paper: Cyclin D1-Smad2/3-Smad4 signaling promotes liver CSC self-renewal and CSC differentiation by Smad inhibitor is a key stage for chemosesitization
Title | Cyclin D1-Smad2/3-Smad4 signaling promotes liver CSC self-renewal and CSC differentiation by Smad inhibitor is a key stage for chemosesitization |
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Authors | |
Issue Date | 2016 |
Publisher | International Society for Stem Cell Research. |
Citation | The 14th Annual Meeting of the International Society for Stem Cell Research (ISSCR 2016), San Francisco, CA., 22-25 June 2016. In Poster Abstract Book, 2016, p. 493-494, abstract no. F2237 How to Cite? |
Abstract | Targeting cancer stemness and induction of differentiation are the new directions for cancer therapy. We investigated the role of cyclin D1-SMAD2/3-SMAD4 signaling pathway in liver cancer stem cells (CSCs) and its potential as therapeutic target. Cyclin D1 dependent phosphorylation of SMAD2/3 and enhanced expression of SMAD4 were detected in HCC spherical cells as well as in over 50% of primary HCC tumor tissues. HCC patients with high levels of cyclin D1, pSMAD2/3, and SMAD4 together displayed a poor overall survival. Overexpression of cyclin D1 conferred liver cancer cells CSC features such as capacity of single sphere formation, increased CD90+ and EpCAM+ liver CSC population, enhanced pluripotency-associated gene and metabolic glycolysis gene expression, which was via activation of SMAD2/3 and SMAD4. Cyclin D1-SMAD2/3-SMAD4 signaling-regulated cancer spheres also showed enhanced epithelial-mesenchymal transition (EMT) phenotype and highly resistant to chemotherapy. Application of TGF-b/SMAD inhibitor (SB431542) inhibited CSC sphere growth moderately although the inhibition was specifically in cyclin D1-expressing but not in parental spheres (a further proof of cyclin D1-mediated activation of SMADs). However, pre-treated with low dose of SMAD inhibitor induced cancer spheres differentiation leading to significant chemosensitization. The same strategy (pre-treatment with low dose of SB431542 followed by cisplatin regularly) significantly decreased tumorigenicity in cyclin D1 sphere-derived xenograft tumor model, with 8 out of 14 (57%) cell injections were tumor free at endpoint, and the formed tumor was only 24% of tumor size of vehicle or cisplatin groups. Interestingly, xenograft tumor was unaffected when applying SMAD inhibitor and cisplatin simultaneously. Mechanistically, SMAD inhibitor reduced CD90+, EpCAN+, and CD133+ liver CSC populations; reduced stemness gene and glycolytic gene expression; reversed EMT phenotype; all these resulting in impaired self-renewal and induced differentiation, which is an effective step for reversing chemoresistance. Together, cyclin D1-SMAD2/3-SMAD4 signaling pathway promotes liver cancer CSC self-renewal. The induction of CSC differentiation by TGF-b/SMAD inhibitor followed by chemotherapy provides a new path for combined therapy. |
Description | Poster: no. F2237 |
Persistent Identifier | http://hdl.handle.net/10722/232572 |
DC Field | Value | Language |
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dc.contributor.author | Wang, X | - |
dc.contributor.author | Wei, X | - |
dc.date.accessioned | 2016-09-20T05:30:57Z | - |
dc.date.available | 2016-09-20T05:30:57Z | - |
dc.date.issued | 2016 | - |
dc.identifier.citation | The 14th Annual Meeting of the International Society for Stem Cell Research (ISSCR 2016), San Francisco, CA., 22-25 June 2016. In Poster Abstract Book, 2016, p. 493-494, abstract no. F2237 | - |
dc.identifier.uri | http://hdl.handle.net/10722/232572 | - |
dc.description | Poster: no. F2237 | - |
dc.description.abstract | Targeting cancer stemness and induction of differentiation are the new directions for cancer therapy. We investigated the role of cyclin D1-SMAD2/3-SMAD4 signaling pathway in liver cancer stem cells (CSCs) and its potential as therapeutic target. Cyclin D1 dependent phosphorylation of SMAD2/3 and enhanced expression of SMAD4 were detected in HCC spherical cells as well as in over 50% of primary HCC tumor tissues. HCC patients with high levels of cyclin D1, pSMAD2/3, and SMAD4 together displayed a poor overall survival. Overexpression of cyclin D1 conferred liver cancer cells CSC features such as capacity of single sphere formation, increased CD90+ and EpCAM+ liver CSC population, enhanced pluripotency-associated gene and metabolic glycolysis gene expression, which was via activation of SMAD2/3 and SMAD4. Cyclin D1-SMAD2/3-SMAD4 signaling-regulated cancer spheres also showed enhanced epithelial-mesenchymal transition (EMT) phenotype and highly resistant to chemotherapy. Application of TGF-b/SMAD inhibitor (SB431542) inhibited CSC sphere growth moderately although the inhibition was specifically in cyclin D1-expressing but not in parental spheres (a further proof of cyclin D1-mediated activation of SMADs). However, pre-treated with low dose of SMAD inhibitor induced cancer spheres differentiation leading to significant chemosensitization. The same strategy (pre-treatment with low dose of SB431542 followed by cisplatin regularly) significantly decreased tumorigenicity in cyclin D1 sphere-derived xenograft tumor model, with 8 out of 14 (57%) cell injections were tumor free at endpoint, and the formed tumor was only 24% of tumor size of vehicle or cisplatin groups. Interestingly, xenograft tumor was unaffected when applying SMAD inhibitor and cisplatin simultaneously. Mechanistically, SMAD inhibitor reduced CD90+, EpCAN+, and CD133+ liver CSC populations; reduced stemness gene and glycolytic gene expression; reversed EMT phenotype; all these resulting in impaired self-renewal and induced differentiation, which is an effective step for reversing chemoresistance. Together, cyclin D1-SMAD2/3-SMAD4 signaling pathway promotes liver cancer CSC self-renewal. The induction of CSC differentiation by TGF-b/SMAD inhibitor followed by chemotherapy provides a new path for combined therapy. | - |
dc.language | eng | - |
dc.publisher | International Society for Stem Cell Research. | - |
dc.relation.ispartof | Annual Meeting of the International Society for Stem Cell Research, ISSCR 2016 | - |
dc.title | Cyclin D1-Smad2/3-Smad4 signaling promotes liver CSC self-renewal and CSC differentiation by Smad inhibitor is a key stage for chemosesitization | - |
dc.type | Conference_Paper | - |
dc.identifier.email | Wang, X: xqwang@hku.hk | - |
dc.identifier.authority | Wang, X=rp00507 | - |
dc.identifier.hkuros | 263651 | - |
dc.identifier.spage | 493, abstract no. F2237 | - |
dc.identifier.epage | 494 | - |
dc.publisher.place | United states | - |