An imbalance in TAZ and YAP expression in hepatocellular carcinoma confers cancer stem cell-like behaviors contributing to disease progression

Hiromitsu Hayashi, Takaaki Higashi, Naomi Yokoyama, Takayoshi Kaida, Keita Sakamoto, Yukiko Fukushima, Takatsugu Ishimoto, Hideyuki Kuroki, Hidetoshi Nitta, Daisuke Hashimoto, Akira Chikamoto, Eiji Oki, Toru Beppu, Hideo Baba

研究成果: Contribution to journalArticle査読

82 被引用数 (Scopus)

抄録

Transcriptional coactivator with PDZ-binding motif (TAZ) and yes-associated protein (YAP) are equivalently placed downstream effectors of the Hippo pathway with oncogenic roles in human cancers. However, the expression profiles of TAZ/YAP differ depending on the cancer cell type, suggesting that these proteins have different roles during cancer progression, yet no studies have examined the biologic significance of the balance between TAZ and YAP expression levels. Here we examined the functional roles of TAZ/YAP in hepatocellular carcinoma progression. We found that TAZ, but not YAP, was predominantly expressed in HCC. TAZ knockdown under normal conditions attenuated cell growth in HCC cells; however, TAZ knockdown combined with 5-fluorouracil treatment significantly increased chemoresistance compared with control cells. Notably, TAZ knockdown induced compensatory YAP expression and was accompanied by upregulation of CD90, a HCC-specific cancer stem cell marker. Continuous treatment with 5-fluorouracil also induced YAP expression and promoted tumor formation in vivo. Conversely, double knockdown of TAZ/YAP reduced chemoresistance and tumorigenicity. Moreover, YAP knockdown aggravated HCC cell growth to a greater degree than TAZ knockdown, and YAP overexpression was strongly associated with poor prognoses in patients with HCC. Collectively, these studies demonstrate that TAZ and YAP exhibit different functional roles in cancer progression, and a shift to predominant YAP expression upon TAZ depletion conferred cancer stem cell-like properties including chemoresistance and tumorigenicity in HCC. Therefore, targeting of both TAZ/YAP will be required for a complete antitumor response in HCC.

本文言語英語
ページ(範囲)4985-4997
ページ数13
ジャーナルCancer Research
75
22
DOI
出版ステータス出版済み - 11 15 2015

All Science Journal Classification (ASJC) codes

  • 腫瘍学
  • 癌研究

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