title: Matrix stiffness-mediated effects on stemness characteristics occurring in HCC cells.
abstract: Matrix stiffness as an important physical attribute of extracellular matrix exerts significant impacts on biological behaviors of cancer cells such as growth, proliferation, motility, metabolism and invasion. However, its influence on cancer stemness still remains elusive. Here, we explore whether matrix stiffness-mediated effects on stemness characteristics occur in HCC cells. As the substrate stiffness increased, HCC cells exhibited high proportion of cells with CD133(+)/EpCAM(+), high expression levels of CD133, EpCAM, Nanog and SOX2, greater self-renewing ability and oxaliplatin resistance. Simultaneously, their phosphorylation levels of Akt and mTOR, as well as p-4E-BP and SOX2 expressions were also obviously upregulated. Conversely, knockdown of integrin β1 partially attenuated higher stiffness-mediated stemness characteristics in HCC cells, and reversed the phosphorylation levels of Akt and mTOR, and expressions of p-4E-BP and SOX2, suggesting that integrin β1 may deliver higher stiffness signal into HCC cells and activate mTOR signaling pathway. Additionally, mTOR inhibitor suppressed the mTOR phosphorylation level and expression levels of p-4E-BP and SOX2 in HCC cells grown on higher stiffness substrate, as well as depressed their stemness properties significantly, favoring a regulating role of mTOR signaling pathway in matrix stiffness-mediated effects on stemness. In summary, matrix stiffness may be involved in the process of stemness regulation via activating integrin β1/Akt/mTOR/SOX2 signaling pathway. To the best of our knowledge, this study first reveals a novel regulating pathway to direct the stemness characteristics in HCC cells.
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: You
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, PR China.
authors.forename: Qiongdan
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, PR China.
authors.forename: Yinying
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, PR China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Interventional Radiology, Shanghai Cancer Center, Fudan University, Shanghai 200032, PR China.
authors.forename: Yaohui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, PR China.
authors.forename: Sifan
authors.initials: S
authors.lastname: Wu
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, PR China.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, PR China.
authors.forename: Yingcong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, PR China.
authors.forename: Tongchun
authors.initials: T
authors.lastname: Xue
authors.affiliation: Department of Oncology, Zhongshan Hospital Subdivision, Fudan University, Shanghai 200052, PR China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, PR China.
authors.forename: Rongxin
authors.initials: R
authors.lastname: Chen
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, PR China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, PR China.
authors.forename: Jiefeng
authors.initials: J
authors.lastname: Cui
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, PR China.
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Ren
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal; D019008:Drug Resistance, Neoplasm; D004548:Elasticity; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D040542:Mechanotransduction, Cellular; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019012:Integrin beta1; D009944:Organoplatinum Compounds; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D000077150:Oxaliplatin; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: hepatocellular carcinoma; integrin β1; mTOR; matrix stiffness; stemness