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REGγ Controls Hippo Signaling and Reciprocal NF-κB-YAP Regulation to Promote Colon Cancer.

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机构： [1]Shanghai Key Laboratory of Regulatory Biology, Institute of BiomedicalSciences, School of Life Sciences, East China Normal University, Shanghai,China [2]Xinhua Hospital Affiliated to Shanghai Jiaotong University, Shanghai,China [3]Department of Orthopedic Oncology, Changzheng Hospital, The SecondMilitary Medical University, Shanghai, China [4]Department of Pathology, TheSecond Chengdu Municipal Hospital, Chengdu, China [5]Department of Molecularand Cellular Biology, Dan L.Duncan Cancer Center, Baylor College of Medicine,Houston, Texas [6]Texas Children's Cancer Center, Department of Pediatrics, DanL.Duncan Cancer Center, Baylor College of Medicine, Houston, Texas [7]The FifthHospital of Shanghai, Fudan University, Shanghai, China [8]Key Laboratory ofEpigenetics and Oncology, The Research Center for Preclinical Medicine, SouthwestMedical University, Sichuan, China

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Purpose: Colorectal cancer is one of the most commonly diagnosed cancers closely associated with inflammation and hyperactive growth. We previously demonstrated a regulatory circuit between the proteasome activator REGγ and NF-kappaB (NF-κB) during colon inflammation, known to be important in the development of colitis-associated cancer as well as sporadic colorectal cancer. How the inflammatory microenvironment affects the Hippo pathway during colorectal cancer development is largely unknown.Experimental Design: Here, we used REGγ-deficient colon cancer cell lines, REGγ knockout mice, and human colorectal cancer samples to identify the novel molecular mechanism by which REGγ functions as an oncoprotein in the development of colorectal cancer.Results: REGγ can directly interact with Lats1 and promote its degradation, which facilitates Yes-associated protein (YAP) activation in colon cancer cells. REGγ deficiency significantly attenuated colon cancer growth, associated with decreased YAP activity. Suppression of tumor growth due to REGγ depletion was overcome by constitutively active YAP. Surprisingly, reciprocal activation of the YAP and NF-κB pathways was observed in human colon cancer cells. REGγ overexpression was found in over 60% of 172 colorectal cancer specimens, highly correlating with the elevation of YAP and p65. Postoperative follow-up revealed a significantly lower survival rate in patients with concomitantly high expression of REGγ, YAP, and p-p65.Conclusions: REGγ could be a master regulator during colorectal cancer development to promote YAP signaling and reinforce cross-talks between inflammation and growth pathways, and REGγ might be a new marker for prognosis of colorectal cancer patients. Clin Cancer Res; 24(8); 2015-25. ©2018 AACR. ©2018 American Association for Cancer Research.

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出版当年[2018]版：

大类 | 1 区

医学

小类 | 1 区肿瘤学

最新[2023]版：

大类 | 1 区

医学

小类 | 1 区肿瘤学

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出版当年[2018]版：

Q1 ONCOLOGY

最新[2023]版：

Q1 ONCOLOGY

影响因子： 10 最新[2023版] 11.1 最新五年平均 8.911 出版当年[2018版] 9.174 出版当年五年平均 10.199 出版前一年[2017版] 10.107 出版后一年[2019版]

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第一作者机构： [1]Shanghai Key Laboratory of Regulatory Biology, Institute of BiomedicalSciences, School of Life Sciences, East China Normal University, Shanghai,China

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通讯机构： [1]Shanghai Key Laboratory of Regulatory Biology, Institute of BiomedicalSciences, School of Life Sciences, East China Normal University, Shanghai,China [5]Department of Molecularand Cellular Biology, Dan L.Duncan Cancer Center, Baylor College of Medicine,Houston, Texas [*1]Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.

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