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Deficiency of the Erc/mesothelin gene ameliorates renal carcinogenesis in Tsc2 knockout mice
Danqing Zhang1, Toshiyuki Kobayashi, Tetsuo Kojima
1Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo, Japan.
Abstract:
Genetic crossing experiments were performed between tuberous sclerosis-2 (Tsc2) KO and expressed in renal carcinoma (Erc) KO mice to analyze the function of the Erc/mesothelin gene in renal carcinogenesis. We found the number and size of renal tumors were significantly less in Tsc2+/-;Erc-/- mice than in Tsc2+/-;Erc+/+ and Tsc2+/-;Erc+/- mice. Tumors from Tsc2+/-;Erc-/- mice exhibited reduced cell proliferation and increased apoptosis, as determined by proliferating cell nuclear antigen (Ki67) and TUNEL analysis, respectively. Adhesion to collagen-coated plates in vitro was enhanced in Erc-restored cells and decreased in Erc-suppressed cells with siRNA. Tumor formation by Tsc2-deficient cells in nude mice was remarkably suppressed by stable knockdown of Erc with shRNA. Western blot analysis showed that the phosphorylation of focal adhesion kinase, Akt and signal transducer and activator of transcription protein 3 were weaker in Erc-deficient/suppressed cells compared with Erc-expressed cells. These results indicate that deficiency of the Erc/mesothelin gene ameliorates renal carcinogenesis in Tsc2 KO mice and inhibits the phosphorylation of several kinases of cell adhesion mechanism. This suggests that Erc/mesothelin may have an important role in the promotion and/or maintenance of carcinogenesis by influencing cell-substrate adhesion via the integrin-related signal pathway.
Insights
Tuberous sclerosis-2 (Tsc2) deficiency leads to kidney cancer. Loss of the Erc/mesothelin gene significantly reduces tumor growth by decreasing cell proliferation and increasing apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tuberous sclerosis-2 (Tsc2) plays a role in renal carcinogenesis.
- The function of the Erc/mesothelin gene in kidney cancer development is not fully understood.
Purpose of the Study:
- To investigate the role of the Erc/mesothelin gene in renal carcinogenesis using a Tsc2 knockout mouse model.
- To analyze the impact of Erc/mesothelin deficiency on tumor growth, cell proliferation, and apoptosis in the context of Tsc2 deficiency.
Main Methods:
- Genetic crossing of Tsc2 KO and Erc KO mice.
- Analysis of tumor number, size, cell proliferation (Ki67), and apoptosis (TUNEL).
- In vitro cell adhesion assays, siRNA-mediated gene suppression, shRNA-mediated gene knockdown, and Western blot analysis of signaling pathways.
Main Results:
- Tsc2+/-;Erc-/- mice showed significantly fewer and smaller renal tumors compared to controls.
- Erc deficiency led to reduced cell proliferation and increased apoptosis in renal tumors.
- Erc knockdown suppressed tumor formation in nude mice and reduced phosphorylation of focal adhesion kinase, Akt, and STAT3.
Conclusions:
- Erc/mesothelin deficiency ameliorates renal carcinogenesis in Tsc2 KO mice.
- Erc/mesothelin promotes renal cancer by influencing cell-substrate adhesion through integrin-related signaling pathways.
