Synergistic function of Smad4 and PTEN in suppressing forestomach squamous cell carcinoma in the mouse.
The genetic bases underlying esophageal tumorigenesis are poorly understood. Our previous studies have shown that coordinated deletion of the Smad4 and PTEN genes results in accelerated hair loss and skin tumor formation in mice. Herein, we exemplify that the concomitant inactivation of Smad4 and PTEN accelerates spontaneous forestomach carcinogenesis at complete penetrance during the first 2 months of age. All of the forestomach tumors were invasive squamous cell carcinomas (SCCs), which recapitulated the natural history and pathologic features of human esophageal SCCs. A small population of the SCC lesions was accompanied by adenocarcinomas at the adjacent submucosa region in the double mutant mice. The rapid progression of forestomach tumor formation in the Smad4 and PTEN double knockout mice corresponded to a dramatic increase in esophageal and forestomach epithelial proliferation. The decreased expression of p27, p21, and p16 together with the overexpression of cyclin D1 contributed cooperatively to the accelerated forestomach tumorigenesis in the double mutant mice. Our results point strongly to the crucial relevance of synergy between Smad4 and PTEN to suppress forestomach tumorigenesis through the cooperative induction of cell cycle inhibitors.
Teng
Yan
Y
Genetic Laboratory of Development and Diseases, Institute of Biotechnology and National Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, P.R. China.
Sun
An-Na
AN
Pan
Xiao-Chen
XC
Yang
Guan
G
Yang
Lei-Lei
LL
Wang
Ming-Rong
MR
Yang
Xiao
X
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D048708:Cell Growth Processes / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D056741:Cyclin D; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D007633:Keratins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics*
D056741:Cyclin D; D016213:Cyclins; D051901:Smad4 Protein; D007633:Keratins; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse