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TGF-beta-independent CTGF induction regulates cell adhesion mediated drug resistance by increasing collagen I in HCC

Authors
Song, YeonhwaKim, Jin-SunChoi, Eun KyungKim, JoonKim, Kang MoSeo, Haeng Ran
Issue Date
28-3월-2017
Publisher
IMPACT JOURNALS LLC
Keywords
tumor spheroids; collagen 1A1; connective tissue growth factor (CTGF); cell adhesion-mediated drug resistance (CAM-DR); hepatocellular carcinoma
Citation
ONCOTARGET, v.8, no.13, pp.21650 - 21662
Indexed
SCIE
SCOPUS
Journal Title
ONCOTARGET
Volume
8
Number
13
Start Page
21650
End Page
21662
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/84103
DOI
10.18632/oncotarget.15521
ISSN
1949-2553
Abstract
Hepatocellular carcinoma (HCC) is resistant to conventional chemotherapeutic agents and remains an unmet medical need. Here, we demonstrate a mechanism of cell adhesion-mediated drug resistance using a variety of HCC spheroid models to overcome environment-mediated drug resistance in HCC. We classified spheroids into two groups, tightly compacted and loosely compacted aggregates, based on investigation of dynamics of spheroid formation. Our results show that compactness of HCC spheroids correlated with fibroblast-like characteristics, collagen 1A1 (COL1A1) content, and capacity for chemoresistance. We also showed that ablation of COL1A1 attenuated not only the capacity for compact-spheroid formation, but also chemoresistance. Generally, connective tissue growth factor (CTGF) acts downstream of transforming growth factor (TGF)-beta and promotes collagen I fiber deposition in the tumor microenvironment. Importantly, we found that TGF-beta-independent CTGF is upregulated and regulates cell adhesion-mediated drug resistance by inducing COL1A1 in tightly compacted HCC spheroids. Furthermore, losartan, which inhibits collagen I synthesis, impaired the compactness of spheroids via disruption of cell-cell contacts and increased the efficacy of anticancer therapeutics in HCC cell line- and HCC patient-derived tumor spheroids. These results strongly suggest functional roles for CTGF-induced collagen I expression in formation of compact spheroids and in evading anticancer therapies in HCC, and suggest that losartan, administered in combination with conventional chemotherapy, might be an effective treatment for liver cancer.
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