Deficiency of the Erc/mesothelin gene ameliorates renal carcinogenesis in Tsc2 knockout mice.

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.

• Authors: Danqing Zhang, Toshiyuki Kobayashi, Tetsuo Kojima, Kenji Kanenishi, Yoshiaki Hagiwara, Masaaki Abe, Hidehiro Okura, Yoshitomo Hamano, Guodong Sun, Masahiro Maeda, Kou-ichi Jishage, Tetsuo Noda, Okio Hino
• Journal: Cancer science (Cancer Sci) Vol. 102 Issue 4 Pg. 720-7 (Apr 2011) ISSN: 1349-7006 [Electronic] England
• PMID: 21205090 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Japanese Cancer Association.

Chemical References

• GPI-Linked Proteins
• Msln protein, mouse
• RNA, Small Interfering
• Tsc2 protein, mouse
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins
• Mesothelin

Topics

• Animals
• Apoptosis
• Carcinoma, Renal Cell (metabolism, pathology, prevention & control)
• Cell Adhesion
• Cell Proliferation
• Cell Transformation, Neoplastic (pathology)
• Female
• GPI-Linked Proteins (antagonists & inhibitors, physiology)
• Kidney Neoplasms (metabolism, pathology, prevention & control)
• Male
• Mesothelin
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Mice, Nude
• Phosphorylation
• RNA, Small Interfering (genetics)
• Signal Transduction
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins (physiology)