The E545K mutation of PIK3CA promotes gallbladder carcinoma progression through enhanced binding to EGFR.
Gallbladder carcinoma (GBC) is the most common malignancy of the bile duct and patients with GBC have extremely poor prognoses. PIK3CA, which encodes the phosphoinositide 3-kinase (PI3K) subunit p110α, is frequently mutated in many cancers, including GBC. The function of the E545K mutation in GBC is not fully understood.



E545K mutation was determined in human GBC tissues by targeted sequencing. The effects of E545K mutation and PI3K selective inhibitor, A66 on GBC cells were evaluated using Cell Counting Kit-8 (CCK-8) cell Viability and transwell assays. The mechanisms of E545K mutation and A66 were analyzed by western blot and co-immunoprecipitation (Co-IP) assay. Subcutaneous xenograft models in nude mice were employed to evaluate the role of E545K mutation and A66 in GBC progression.



The rate of PIK3CA E545K mutation in GBC patients was 6.15 %. And the survival of GBC patients was correlated with E545K mutation significantly (P < 0.05). The E545K mutation promoted proliferation, migration and invasion of GBC cells in vitro and tumor proliferation in vivo. A66 suppressed proliferation of GBC cells in vitro and tumor proliferation in vivo.



The prognoses of patients with E545K mutation were worse than patients without this mutation. The E545K mutation promoted GBC progression through enhanced binding to EGFR and activating downstream akt activity. The PI3K selective inhibitor, A66, suppressed gallbladder carcinoma proliferation.
Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China.|Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China.
Shuai
S
Zhao
Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China.|Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China.
Yang
Y
Cao
Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China.|Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China.
Shi-Bo
SB
Liu
Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China.|Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China.
Xu-An
XA
Wang
Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China.|Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China.
Run-Fa
RF
Bao
Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China.|Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China.
Yi-Jun
YJ
Shu
Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China.|Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China.
Yun-Ping
YP
Hu
Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China.|Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China.
Yi-Jian
YJ
Zhang
Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China.|Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China.
Lin
L
Jiang
Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China.|Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China.
Fei
F
Zhang
Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China.|Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China.
Hai-Bin
HB
Liang
Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China.|Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China.
Huai-Feng
HF
Li
Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China.|Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China.
Qiang
Q
Ma
Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China.|Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China.
Yi
Y
Xu
Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China.|Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China.
Zheng
Z
Wang
Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China.|Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China.
Yi-Chi
YC
Zhang
Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China. fcyc6110@126.com.
Lei
L
Chen
Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China. jzhou2016@163.com.
Jian
J
Zhou
Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China. liuybphd@126.com.
Ying-Bin
YB
Liu
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005706:Gallbladder Neoplasms / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011379:Prognosis; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011485:Protein Binding; D015398:Signal Transduction; D016019:Survival Analysis; D013844:Thiazoles / Q000494:pharmacology
C000592780:N1-(2-(t-butyl)-4'-methyl-(4,5'-bithiazol)- 2'-yl)pyrrolidine-1,2-dicarboxamide; D013844:Thiazoles; D011392:Proline; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors
Cancer; EGFR; Gallbladder carcinoma; PI3K