title: PINCH-2 presents functional copy number variation and suppresses migration of colon cancer cells by paracrine activity.
abstract: In recent years, characterization of cancer and its environment has become necessary. However, studies of the cancer microenvironment remain insufficient. Copy number variations (CNVs) occur in 40% of cancer-related genes, but few studies have reported the correlation between CNVs in morphologically normal tissues adjacent to cancer and cancer progression. In this study, we evaluated cancer cell migration and invasion according to the genetic differences between cancer tissues and their surrounding normal tissues. To study the field cancerization effect, we screened 89 systemic metastasis-related CNVs from morphologically normal tissues adjacent to colon cancers. Among these CNVs, LIM and senescent cell antigen-like domain 2 (PINCH-2) showed copy number amplification and upregulation of mRNA in the nonrelapsed group compared to the systemic relapse group. PINCH-2 expression in colon cancer cells was lower than that in normal epithelial colon cells at both the protein and mRNA levels. Suppression of PINCH-2 resulted in decreased formation of the PINCH-2-IPP (PINCH-2, integrin-linked kinase and α-parvin) complex and reciprocally increased formation of the PINCH-1-IPP complex. Although PINCH-2 expression of survival pathway-related proteins (Akt and phospho-Akt) did not change upon suppression of PINCH-2 expression, cell migration-related proteins [matrix-metalloproteinase (MMP)-9 and -11] were upregulated through autocrine and paracrine activation. Thus, PINCH-2 participates in decreased systemic recurrence by competitively regulating IPP complex formation with PINCH-1, thereby suppressing autocrine and paracrine effects on motility in colon cancer. This genetic change in morphologically normal tissue suggests a field cancerization effect of the tumor microenvironment in cancer progression.
authors.affiliation: National Biochip Research Center, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Korea; Cancer Metastasis Research Center, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Korea; Yonsei Cancer Research Institute, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Korea.
authors.forename: Chan Hee
authors.initials: CH
authors.lastname: Park
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
authors.forename: Joong Bae
authors.initials: JB
authors.lastname: Ahn
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Shin
authors.forename: Woo Sun
authors.initials: WS
authors.lastname: Kwon
authors.forename: Tae Soo
authors.initials: TS
authors.lastname: Kim
authors.forename: Sungwhan
authors.initials: S
authors.lastname: An
authors.forename: Nam Kyu
authors.initials: NK
authors.lastname: Kim
authors.forename: Woo-ick
authors.initials: WI
authors.lastname: Yang
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Chung
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D056915:DNA Copy Number Variations; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D009362:Neoplasm Metastasis; D019899:Paracrine Communication; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C118205:IPP protein, human; D060588:LIM Domain Proteins; C088088:LIMS1 protein, human; C490235:LIMS2 protein, human; D008565:Membrane Proteins
keywords: IPP complex; PINCH-2; Systemic metastasis; array-CGH; colon cancer; copy number variants