GENERATION AND ANALYSES OF krasV12 TRANSGENIC ZEBRAFISH TO STUDY INTESTINE TUMORIGENESIS

Mutations in KRAS contribute to 40% of colorectal cancer cases. To explore the mechanism of krasV12 oncogene in intestine cancer we generated a novel inducible model in zebrafish. The stable transgenic zebrafish expressed krasV12 under a gut specific promoter and the EGFPkrasV12 enabled live imaging. The expression of oncogenic krasV12 caused highly proliferative epithelial outgrowths in to the lumen. Long term induction of krasV12 resulted in tubular adenoma of the adult fish along with significant increase in p-Erk and downregulation of E-cadherin in larvae. Our results demonstrate that overexpression of krasV12 induces intestinal tumorigenesis in zebrafish. We have assessed additive effects of krasV12 overexpression in pro-tumorigenic microenvironments, namely tp53 mutation and inflammation. Larvae immunohistochemistry and adult histopathology data show that the sensitized background enhances effects of tumorigenesis by reducing tumor latency. Hence our intestine-specific inducible krasV12 provides an ideal framework to test anti-cancer drug targets against colorectal cancer.

Author dc:creator

• DIVYA RAGHURAM

• Zebrafish, Intestine, Cancer, Transgenic, kras, Inducible