The Role And Molecular Mechanism Of IQGAP3 In The Proliferation And Migration Of Colorectal Cancer

BACKGROUND AND OBJECTIVE:Colorectal cancer(CRC)is one of the most commonly malignant tumors,the morbidity and the mortality is among the upper third and fourth of all tumors,respectively.And the mortality rate is only after lung cancer,liver cancer and gastric cancer.In China,the morbidity and mortality of CRC have been growing since 2010,thus CRC is the leading cause of death in cancer patients.And the age at onset is becoming younger and younger.CRC not only reduced the quality of life of patients,but also brought a heavy financial burden to the community.However,the underlying mechanism of the occurrence and development of CRC has not yet been fully elucidated.Carcinogenesis of CRC is a complex process with multistage,multistep,following the "normal-hyperplasia-adenoma-cancer" process.The main mechanisms include chromosome instability(CNI),microstatellite instability(MSI),CpG island methylator phenotype(CIMP)and serrated pathway.In addition,there is a part of CRC whose occurrence and development involving two and more mechanisms above.Metastasis is the leading cause of death in CRC clinically,which mainly includes the local invasion of tumour cells,intravasation,metastasis with the blood in blood vessels,extravasation from blood vessels and form new colonization and proliferation of metastases in distant organs eventually.There are many complex factors in this process.Therefore,it has important scientific significance and clinical value for achieving early diagnosis of colorectal cancer,estimating prognosis and taking targeted therapy to study the molecular mechanism of the occurrence and development of CRC,in particular the mechanism of invasion and metastasis and to find valuable molecular markers.The IQGAP3 gene is located on human chromosome 1q21.3.And it encodes a protein whose size is about 180KD,containing 1631 amino acids,and whose expression is mainly in the intestinal,liver and brain,lung and so on.At present,the research of its function mainly focuses on neurite outgrowth,cytoskeleton formation etc.The studies also found that the expression disorder of IQGAP3 protein participated in the liver cancer and lung cancer.However,the effects of the disorder on the occurrence and development of CRC has been unclear so far.Thus the study intends to explore the function and molecular mechanism of IQGAP3 in the occurrence and evolution of CRC.METHODS:1.TCGA databases and Immunohistochemistry(IHC)were used to analyze the expression of IQGAP3 in paraffin-embedded CRC tissues and matched normal tissues.2.Real-time quantitative PCR(RT-PCR)and Western blot was used to detect IQGAP3 expression in freshed CRC tissues and cell lines,and the CRC cell lines with IQGAP3 overexpression and IQGAP3 knockdown were constructed.3.The proliferation and migration ability were measured by MTT assay,platelet cloning,soft agar cloning and nude mice subcutaneous tumorigenesis,scratches heal assay and transwell chamber assay.4.GSEA gene enrichment was used to analyse the involved biological processes of IQGAP3,flow cytometry and Western blot were used to study the possible targets of related signaling pathway of IQGAP3 overexpression and knockdown,and so we discussed the occurrence and migration of CRC with the participation of IQGAP3.RESULTS:1.The expression of IQGAP3 in colorectal cancer tissues and cancer cells is higher than normal tissues and cell;2.The expression of IQGAP3 in colorectal cancer cells is higher than normal cell;3.IQGAP3 overexpression promotes the abilities of proliferation and migration of colorectal cancer cells markedly,and IQGAP3 knockdown suppresses the abilities markedly;4.IQGAP3 influences the activity of the KRAS signaling pathway and its downstream target genes in colorectal cancer cells.CONCLUSION:1.The expression of IQGAP3 in CRC tissue were higher than that in paired normal CRC tissue.2.The CRC cells with IQGAP3 overexpression increased the ability of proliferation and proliferation,but cells with IQGAP3 knockdown decreased.3.IQGAP3 promotes the ability of proliferation and migration of CRC cells by KRAS/AKT and KRAS/Rac1?CDC42 signaling pathway.