Open AccessMetastatic ability and the epithelial‐mesenchymal transition in induced cancer stem‐like hepatoma cells
Author(s) -
Nishiyama Mitsuo,
Tsunedomi Ryouichi,
Yoshimura Kiyoshi,
Hashimoto Noriaki,
Matsukuma Satoshi,
Ogihara Hiroyuki,
Kanekiyo Shinsuke,
Iida Michihisa,
Sakamoto Kazuhiko,
Suzuki Nobuaki,
Takeda Shigeru,
Yamamoto Shigeru,
Yoshino Shigefumi,
Ueno Tomio,
Hamamoto Yoshihiko,
Hazama Shoichi,
Nagano Hiroaki
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13527
Subject(s) - epithelial–mesenchymal transition , biology , cancer stem cell , metastasis , cancer cell , cancer , cancer research , microbiology and biotechnology , stem cell , genetics
Cancer stem cells ( CSC s) are thought to play important roles in cancer malignancy. Previously, we successfully induced sphere cancer stem‐like cells ( CSLC s) from several cell lines and observed the property of chemoresistance. In the present study, we examined the metastatic potential of these induced CSLC s. Sphere cancer stem‐like cells were induced from a human hepatoma cell line ( SK ‐ HEP ‐1) in a unique medium containing neural survival factor‐1. Splenic injection of cells into immune‐deficient mice was used to assess hematogenous liver metastasis. Transcriptomic strand‐specific RNA ‐sequencing analysis, quantitative real‐time PCR , and flow cytometry were carried out to examine the expression of epithelial‐mesenchymal transition ( EMT )‐related genes. Splenic injection of CSLC s resulted in a significantly increased frequency of liver metastasis compared to parental cancer cells ( P < .05). In CSLC s, a mesenchymal marker, Vimentin, and EMT ‐promoting transcription factors, Snail and Twist1, were upregulated compared to parental cells. Correspondingly, significant enrichment of the molecular signature of the EMT in CSLC s relative to parental cancer cells was shown ( q < 0.01) by RNA ‐sequencing analysis. This analysis also revealed differential expression of CD 44 isoforms between CSLC s and parental cancer cells. Increasing CD 44 isoforms containing an extra exon were observed, and the standard CD 44 isoform decreased in CSLC s compared to parental cells. Interestingly, another CD 44 variant isoform encoding a short cytoplasmic tail was also upregulated in CSLC s (11.7‐fold). Our induced CSLC s possess an increased liver metastatic potential in which promotion of the EMT and upregulation of CD 44 variant isoforms, especially short‐tail, were observed.