Specific microRNA–mRNA Regulatory Network of Colon Cancer Invasion Mediated by Tissue Kallikrein–Related Peptidase 61

Autor: Sells, Earlphia, Pandey, Ritu, Chen, Hwudaurw, Skovan, Bethany A., Cui, Haiyan, Ignatenko, Natalia A.
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Original article
EMT
epithelial- mesenchymal transition
VCAN
versican
Mice
FOS
FBJ murine osteosarcoma viral oncogene homolog
PAM
peptidylglycine alpha-amidating monooxygenase
Transforming Growth Factor beta
Cell Line
Tumor
GAPDH
glyceraldehyde 3′-phosphate dehydrogenase
Animals
Humans
Gene Regulatory Networks
Neoplasm Invasiveness
RNA
Messenger
Neoplasm Metastasis
Cell Proliferation
EHF
Ets homologous factor
HMGA2
high-mobility group AT-hook 2
HCT116 Cells
Xenograft Model Antitumor Assays
Gene Expression Regulation
Neoplastic
MicroRNAs
KLK6
kallikrein-related peptidase 6
Gene Knockdown Techniques
CRC
colorectal cancer
Colonic Neoplasms
RUNX2
transforming growth factor beta 2 (TGF-β2) Runt–related transcription factor 2
Kallikreins
RIT1
Ric-related gene expressed throughout the organism
Signal Transduction
Zdroj: Neoplasia (New York, N.Y.)
ISSN: 1476-5586
1522-8002
Popis: Metastatic colon cancer is a major cause of deaths among colorectal cancer (CRC) patients. Elevated expression of kallikrein 6 (KLK6), a member of a kallikrein subfamily of peptidase S1 family serine proteases, has been reported in CRC and is associated with low patient survival rates and poor disease prognosis. We knocked down KLK6 expression in HCT116 colon cancer cells to determine the significance of KLK6 expression for metastatic dissemination and to identify the KLK6-associated microRNAs (miRNAs) signaling networks in metastatic colon cancer. KLK6 suppression resulted in decreased cells invasion in vitro with a minimal effect on the cell growth and viability. In vivo, animals with orthotopic colon tumors deficient in KLK6 expression had the statistically significant increase in survival rates (P = .005) and decrease in incidence of distant metastases. We further performed the integrated miRNA and messenger RNA (mRNA) expression profiling to identify functional miRNA-mRNA interactions associated with KLK6-mediated invasiveness of colon cancer. Through bioinformatics analysis we identified and functionally validated the top two up-regulated miRNAs, miR-182 and miR-203, and one down-regulated miRNA, miRNA-181d, and their seven mRNA effectors. The established miRNA-mRNA interactions modulate cellular proliferation, differentiation and epithelial–mesenchymal transition (EMT) in KLK6-expressing colon cancer cells via the TGF-β signaling pathway and RAS-related GTP-binding proteins. We confirmed the potential tumor suppressive properties of miR-181d and miR-203 in KLK6-expressing HCT116 cells using Matrigel invasion assay. Our data provide experimental evidence that KLK6 controls metastasis formation in colon cancer via specific downstream network of miRNA-mRNA effectors.
Databáze: OpenAIRE
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