title: An Imbalance in TAZ and YAP Expression in Hepatocellular Carcinoma Confers Cancer Stem Cell-like Behaviors Contributing to Disease Progression.
abstract: 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.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan. Department of Surgery, Saiseikai Kumamoto Hospital, Kumamoto, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Higashi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Yokoyama
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kaida
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Fukushima
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Ishimoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kuroki
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Nitta
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hashimoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Chikamoto
authors.affiliation: Departments of Surgery and Science Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Oki
authors.affiliation: Department of Multidisciplinary Treatment for Gastroenterological Cancer, Kumamoto University Hospital, Kumamoto, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Beppu
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan. hdobaba@kumamoto-u.ac.jp.
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010750:Phosphoproteins / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D059467:Transcriptome; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human