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ANO9/TMEM16J promotes tumourigenesis via EGFR and is a novel therapeutic target for pancreatic cancer

 Ikhyun Jun  ;  Hyung Soon Park  ;  He Piao  ;  Jung Woo Han  ;  Min Ji An  ;  Byeong Gyu Yun  ;  Xianglan Zhang  ;  Yong Hoon Cha  ;  You Keun Shin  ;  Jong In Yook  ;  Jinsei Jung  ;  Heon Yung Gee  ;  Joon Seong Park  ;  Dong Sup Yoon  ;  Hei-Cheul Jeung  ;  Min Goo Lee 
 BRITISH JOURNAL OF CANCER, Vol.117(12) : 1798-1809, 2017 
Journal Title
Issue Date
Adult ; Aged ; Aged, 80 and over ; Animals ; Anoctamins/genetics* ; Anoctamins/metabolism* ; Anti-Bacterial Agents/therapeutic use ; Antineoplastic Agents/pharmacology ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Carcinogenesis ; Carcinoma, Pancreatic Ductal/drug therapy ; Carcinoma, Pancreatic Ductal/genetics* ; Carcinoma, Pancreatic Ductal/metabolism* ; Cell Line, Tumor ; Cell Proliferation/genetics ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/pharmacology ; Disease-Free Survival ; Doxycycline/therapeutic use ; Erlotinib Hydrochloride/pharmacology ; Female ; Gene Knockdown Techniques ; HEK293 Cells ; Humans ; Male ; Membrane Proteins/genetics ; Membrane Proteins/metabolism* ; Mice ; Middle Aged ; Neoplasm Transplantation ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/genetics* ; Pancreatic Neoplasms/metabolism* ; Phospholipid Transfer Proteins/genetics* ; Phospholipid Transfer Proteins/metabolism* ; Prognosis ; RNA, Messenger/metabolism ; Receptor, Epidermal Growth Factor/antagonists & inhibitors ; Receptor, Epidermal Growth Factor/metabolism* ; Survival Rate ; Tumor Stem Cell Assay
BACKGROUND: Anoctamin (ANO)/transmembrane member 16 (TMEM16) proteins mediate diverse physiological and pathophysiological functions including cancer cell proliferation. The present study aimed to identify the role of ANOs in pancreatic cancer.

METHODS: In an initial screen of ANOs, ANO9/TMEM16J was overexpressed in pancreatic cancer cells, and its role in the pathogenesis of pancreatic cancer was evaluated using an integrated in vitro and in vivo approach. To determine clinical relevance of the experimental findings, the prognostic value of ANO9 was evaluated in patients with pancreatic cancer.

RESULTS: The ANO9 mRNA and protein levels were increased in pancreatic cancer-derived cells. Exogenous expression of ANO9 in PANC-1 cells significantly increased cell proliferation in cell cultures and in mice. In contrast, knockdown of ANO9 in AsPC-1, BxPC-3, and Capan-2 cells strongly inhibited cell proliferation. Mechanistic analysis suggested that physical association of ANO9 with epidermal growth factor receptor (EGFR) underlies ANO9-induced cell proliferation. Knockdown of ANO9 augmented the effects of the EGFR inhibitor and the cytotoxic agent on pancreatic cancer cell proliferation. In addition, high ANO9 expression is a poor prognostic factor in patients with pancreatic cancer.

CONCLUSIONS: The ANO9/TMEM16J appears to be a clinically useful prognostic marker for pancreatic cancer and a potential therapeutic target.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Piao, He(박학) ORCID logo https://orcid.org/0000-0002-1817-3167
Park, Hyung Soon(박형순)
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Jun, Ik Hyun(전익현) ORCID logo https://orcid.org/0000-0002-2160-1679
Jung, Jinsei(정진세) ORCID logo https://orcid.org/0000-0003-1906-6969
Jeung, Hei Cheul(정희철) ORCID logo https://orcid.org/0000-0003-0952-3679
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
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