Open AccessThe SHH /Gli axis regulates CD 90‐mediated liver cancer stem cell function by activating the IL 6/ JAK 2 pathway
Author(s) -
Zhang Ketao,
Che Siyao,
Pan Chuzhi,
Su Zheng,
Zheng Shangyou,
Yang Shanglin,
Zhang Huayao,
Li Wenda,
Wang Weidong,
Liu Jianping
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13651
Subject(s) - cancer stem cell , liver cancer , cancer research , gene knockdown , gli1 , stem cell , sonic hedgehog , cancer , cancer cell , biology , gli3 , pancreatic cancer , chemistry , cd44 , cell , microbiology and biotechnology , hedgehog signaling pathway , apoptosis , signal transduction , gene expression , biochemistry , gene , hepatocellular carcinoma , genetics , repressor
The cell surface antigen CD 90 has recently been established as a promising marker for liver cancer stem cells. This study aimed to investigate potential implications of SHH /Gli signalling in CD 90+ liver cancer stem cells. Correlation of the expression of SHH signalling components and CD 90 in liver cancer cells and clinical tissues, as well as in enriched CD 90+ liver cancer stem cells and the TCGA database, were analysed by quantitative RT ‐ PCR , Western blotting and flow cytometry. Functional analysis was conducted by si RNA ‐mediated CD 90, Gli1 and Gli3 gene knockdown, SHH treatment and application of the JAK 2 inhibitor AZD 1480 and IL 6 neutralizing antibody in CD 90+ liver cancer stem cells, followed by cell proliferation, migration, sphere formation and tumorigenicity assays. CD 90 expression exhibited a high positive correlation with Gli1 and Gli3 in multiple liver cancer cell lines and human cancerous liver tissues, both of which showed a significant increase in liver cancer. Analysis of TCGA data revealed an association of CD 90, Gli1 and Gli3 with a short overall survival and positive correlation between CD 90 expression and Gli3 expression level. The stem cell potentials of CD 90+ 97L liver cancer cells were greatly impaired by Gli1/3 knockdown with si RNA but enhanced by SHH treatment. Application of the JAK 2 inhibitor AZD 1480 and IL 6 neutralizing antibody showed the CD 90 and SHH /Gli‐regulated liver cancer stem cell functions were mediated by the IL 6/ JAK 2/ STAT 3 pathway. The stem cell properties of CD 90+ liver cancer cells are regulated by the downstream SHH /Gli and IL 6/ JAK 2/ STAT 3 signalling pathways.