Role of IQGAP2 depending on ras subcellular localization : implications in thyroid cancer

Abstract

Thyroid cancer is the most common endocrine malignancy worldwide. In 70% of the cases, it is related to mutation that activate the Ras-Raf-MEK-ERK cascade, a well-known pathway related with cellular transformation, proliferation and tumour progression. The high frequency of aberrant Ras expression in this pathway results in the more aggressive and worse prognosis thyroid carcinomas. Moreover, Ras proteins are distributed in different types of plasma membrane and endomembrane microdomains: endoplasmic reticulum, lipid rafts, disorder membrane and the Golgi complex. It has been shown that compartmentalization dictates the use of Ras effectors, the intensity of their signals and consequently the biological response of the cells. Furthermore, the last studies shown the participation of scaffold proteins in the spreading of site-specific Ras signals to enhance the activation of ERK targets. However, although IQGAP2 expression is downregulated in some neoplasms, their role in thyroid cancer is not well documented yet. We have generated by CRISPR/CAS9 genome editing an IQGAP2 knock out stable PCCL3 cells lines expressing H-RasV12 in the different subcellular localizations, with the purpose of study their proliferative, migrative and invasive behavior. Moreover, we have used the chick chorioallantoic membrane embryo model to determine the role of IQGAP2 in thyroid tumor progression in vivo. This information can contribute to determine the participation of IQGAP2 in thyroid cancer and develop new cancer therapies where therapeutic agents are used to suppress the oncogenic signaling through the Ras-ERK axis, hopefully improving tumor control and survival of thyroid cancer patients in the future.