Universität zu Köln

Gao, Xiaomei, Sheng, Yuanyuan, Yang, Jing, Wang, Chaoqun, Zhang, Rui, Zhu, Ying, Zhang, Ze, Zhang, Kaili, Yan, Shican, Sun, Haoting, Wei, Jinwang, Wang, Xuan, Yu, Xinxin, Zhang, Yu, Luo, Qin, Zheng, Yan, Qiao, Peng, Zhao, Yue, Dong, Qiongzhu and Qin, Lunxiu (2018). Osteopontin alters DNA methylation through up-regulating DNMT1 and sensitizes CD133+/CD44+cancer stem cells to 5 azacytidine in hepatocellular carcinoma. J. Exp. Clin. Cancer Res., 37. LONDON: BMC. ISSN 1756-9966

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Abstract

Background: In hepatocellular carcinoma (HCC), CD133+/CD44+ cells are one subgroup with high stemness and responsible for metastatic relapse and resistance to treatment. Our previous studies have demonstrated that osteopontin (OPN) plays critical roles in HCC metastasis. We further investigated the molecular mechanism underlying the role of OPN in regulating the stemness of HCC epigenetically and explored possible targeting strategy. Methods: CD133+/CD44+ subgroup sorting from HCC cell lines and HCC tissues was used to investigate the effects of OPN knockdown on stemness. iTRAQ and MedIP-sequencing were applied to detect the protein profile and epigenetic modification of CD133+/CD44+ subgroup with or without OPN knockdown. The antitumor effects of 5 Azacytidine were examined in cultured HCC cells and patient derived xenograft (PDX) models. Results: OPN was accumulated in CD133+/CD44+ subgroup of HCC cells. Knocking down OPN significantly inhibited the sphere formation and stemness-related genes expression, and delayed tumor initiation of CD133+/CD44+ subgroup of HCC cells. Employing MedIP-sequencing, dot blot and iTRAQ analyses of CD133+/CD44+ SCR and CD133+/CDM44+ shOPN cells, we found that OPN knockdown leaded to reduction in DNA methylation with particular enrichment in CGI. Meanwhile, DNA (cytosine-5)-methyltransferase 1 (DNMT1), the main methylation maintainer, was downregulated via proteomics analysis, which mediated OPN altering DNA methylation. Furthermore, DNMT1 upregulation could partially rescue the properties of CD133+/CD44+ shOPN cells. Both in vitro and in vivo assays showed that CD133+/CD44+ cells with high OPN levels were more sensitive to DNA methylation inhibitor, 5 Azacytidine (5 Aza). The above findings were validated in HCC primary cells, a more clinically relevant model. Conclusions: OPN induces methylome reprogramming to enhance the stemness of CD133+/CD44+ subgroup and provides the therapeutic benefits to DNMT1 targeting treatment in HCC.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Gao, Xiaomei UNSPECIFIED UNSPECIFIED UNSPECIFIED Sheng, Yuanyuan UNSPECIFIED UNSPECIFIED UNSPECIFIED Yang, Jing UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Chaoqun UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Rui UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhu, Ying UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Ze UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Kaili UNSPECIFIED UNSPECIFIED UNSPECIFIED Yan, Shican UNSPECIFIED UNSPECIFIED UNSPECIFIED Sun, Haoting UNSPECIFIED UNSPECIFIED UNSPECIFIED Wei, Jinwang UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Xuan UNSPECIFIED UNSPECIFIED UNSPECIFIED Yu, Xinxin UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Yu UNSPECIFIED UNSPECIFIED UNSPECIFIED Luo, Qin UNSPECIFIED UNSPECIFIED UNSPECIFIED Zheng, Yan UNSPECIFIED UNSPECIFIED UNSPECIFIED Qiao, Peng UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhao, Yue UNSPECIFIED UNSPECIFIED UNSPECIFIED Dong, Qiongzhu UNSPECIFIED UNSPECIFIED UNSPECIFIED Qin, Lunxiu UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-179337
DOI:	10.1186/s13046-018-0832-1
Journal or Publication Title:	J. Exp. Clin. Cancer Res.
Volume:	37
Date:	2018
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1756-9966
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SOLID TUMORS; LIVER-CANCER; METASTASIS; GROWTH; PROMOTES; NICHE; ANGIOGENESIS; ACTIVATION; TRANSITION; THERAPIES Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17933