title: Proteomics identification of ITGB3 as a key regulator in reactive oxygen species-induced migration and invasion of colorectal cancer cells.
abstract: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and second in females worldwide. Unfortunately 40-50% of patients already have metastatic disease at presentation when prognosis is poor with a 5-year survival of <10%. Reactive oxygen species (ROS) have been proposed to play a crucial role in tumor metastasis. We now show that higher levels of ROS accumulation are found in a colorectal cancer-derived metastatic cell line (SW620) compared with a cell line (SW480) derived from the primary lesion from the same patient. In addition, ROS accumulation can affect both the migratory and invasive capacity of SW480 and SW620 cells. To explore the molecular mechanism underlying ROS-induced migration and invasion in CRC, we have compared protein expression patterns between SW480 and SW620 cells using a two-dimensional electrophoresis-based proteomics strategy. A total of 63 altered proteins were identified from tandem MS analysis. Cluster analysis revealed dysregulated expression of multiple redox regulative or ROS responsive proteins, implicating their functional roles in colorectal cancer metastasis. Molecular and pathological validation demonstrated that altered expression of PGAM1, GRB2, DJ-1, ITGB3, SOD-1, and STMN1 was closely correlated with the metastatic potential of CRC. Functional studies showed that ROS markedly up-regulated expression of ITGB3, which in turn promoted an aggressive phenotype in SW480 cells, with concomitant up-regulated expression of STMN1. In contrast, knockdown of ITGB3 expression could mitigate the migratory and invasive potential of SW620 or H(2)O(2)-treated SW480 cells, accompanied by down-regulated expression of STMN1. The function of ITGB3 was dependent on the surface expression of integrin αvβ3 heterodimer. Furthermore, STMN1 expression and the PI3K-Akt-mTOR pathway were found to be involved in ROS-induced and ITGB3-mediated migration and invasion of colorectal cancer cells. Taken together, these studies suggest that ITGB3 plays an important role in ROS-induced migration and invasion in CRC.
authors.affiliation: The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Lei
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.forename: Cong
authors.initials: C
authors.lastname: Gao
authors.forename: Quek Choon
authors.initials: QC
authors.lastname: Lau
authors.forename: Hua
authors.initials: H
authors.lastname: Pan
authors.forename: Ke
authors.initials: K
authors.lastname: Xie
authors.forename: Jingyi
authors.initials: J
authors.lastname: Li
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Na
authors.initials: N
authors.lastname: Xie
authors.forename: Huey Shan
authors.initials: HS
authors.lastname: Nai
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Dong
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
authors.forename: Edouard C
authors.initials: EC
authors.lastname: Nice
authors.forename: Canhua
authors.initials: C
authors.lastname: Huang
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D040901:Proteomics; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism*
chemical_list: C061248:ITGB3 protein, human; D039661:Integrin beta3; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide