IQGAP3 Regulates Tumorigenesis via Ras and TGFb Signaling in Gastric Cancer

Authors:
Mitsuhiro SHIMURA¹, Pang SHUCHIN¹, Junichi MATSUO¹, Linda Shyue Huey CHUANG¹, Yoshiaki ITO¹


Affliations:
¹Cancer Science Institute of Singapore, National University of Singapore, Singapore


Corresponding email address:
Mitsuhiro SHIMURA (csimsh@nus.edu.sg)

Abstract

IQ motif-containing GTPase-activating protein 3 (IQGAP3) is a member of the IQGAP family, and is identified as a cytoskeletal protein/a scaffold protein. The interaction between IQGAP3 and Ras/ERK pathway in normal epithelial cells was reported before, but the function of IQGAP3 in gastric cancer (GC) is still unknown. The aim of this study is to elucidate the function of IQGAP3 in GC. According to Stomach Adenocarcinoma of TCGA Pan Cancer Atlas, frequent gene mutations were found in genes belonging to TP53 (60.1%), RTK-Ras (51.8%), TGFb pathway (36.4%), and PI3K (31.1%). The GSEA analysis from RNA sequence data of three GC cell lines (AGS, NUGC3, and Hs746T) revealed that Kras signaling was consistently and significantly downregulated after siIQGAP3 knock down (KD). In addition, RNA sequence data indicated that IQGAP3 was also associated with epithelial mesenchymal transition and TGFb signaling. According to the results of Western blot in AGS, NUGC3, and Hs746T, IQGAP3 KD significantly suppressed phosphorylation of ERK and AKT signaling, but didn’t suppress phosphorylation of SMAD signaling. On the other hand, IQGAP3 KD suppressed invasion/migration function after TGFb treatment although TGFb treatment significantly upregulate invasion/migration ability of GC cell lines. The cooperation between MEK/ERK signaling and TGFb signaling contributes to the activation of invasion/migration, and IQGAP3 KD suppress this interaction via blocking Ras signaling. Furthermore, the subcutaneous tumors from sh-IQGAP3 KD GC cell lines using lentivirus were significantly smaller than the one from sh-Controlin vivo. IQGAP3 plays an important role in signal transduction of GC cells as a scaffold protein. IQGAP3 is strongly associated with the phosphorylation of Ras signaling and regulates the function of TGFb signaling via Ras signaling. Since mutation rates of Ras and TGFb pathway in GC are high, IQGAP3 can be a great choice of the therapy targets in GC.