Specific microRNA–mRNA Regulatory Network of Colon Cancer Invasion Mediated by Tissue Kallikrein–Related Peptidase 6

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 disea...

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Main Authors: Earlphia Sells, Ritu Pandey, Hwudaurw Chen, Bethany A. Skovan, Haiyan Cui, Natalia A. Ignatenko
Format: Article
Language:English
Published: Elsevier 2017-05-01
Series:Neoplasia: An International Journal for Oncology Research
Online Access:http://www.sciencedirect.com/science/article/pii/S1476558616303335
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spelling doaj-ac89b49ebb8a45d9904f5c64d47a615b2020-11-24T22:21:00ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022017-05-0119539641110.1016/j.neo.2017.02.003Specific microRNA–mRNA Regulatory Network of Colon Cancer Invasion Mediated by Tissue Kallikrein–Related Peptidase 6Earlphia Sells0Ritu Pandey1Hwudaurw Chen2Bethany A. Skovan3Haiyan Cui4Natalia A. Ignatenko5Biochemistry and, Molecular and Cellular Biology Graduate Program, Department of Molecular and Cellular Biology, College of Science, University of Arizona, Tucson, AZ, USAUniversity of Arizona, Cancer Center, University of Arizona, Tucson, AZ, USAUniversity of Arizona, Cancer Center, University of Arizona, Tucson, AZ, USAUniversity of Arizona, Cancer Center, University of Arizona, Tucson, AZ, USAUniversity of Arizona, Cancer Center, University of Arizona, Tucson, AZ, USADepartment of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USAMetastatic 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.http://www.sciencedirect.com/science/article/pii/S1476558616303335
collection DOAJ
language English
format Article
sources DOAJ
author Earlphia Sells
Ritu Pandey
Hwudaurw Chen
Bethany A. Skovan
Haiyan Cui
Natalia A. Ignatenko
spellingShingle Earlphia Sells
Ritu Pandey
Hwudaurw Chen
Bethany A. Skovan
Haiyan Cui
Natalia A. Ignatenko
Specific microRNA–mRNA Regulatory Network of Colon Cancer Invasion Mediated by Tissue Kallikrein–Related Peptidase 6
Neoplasia: An International Journal for Oncology Research
author_facet Earlphia Sells
Ritu Pandey
Hwudaurw Chen
Bethany A. Skovan
Haiyan Cui
Natalia A. Ignatenko
author_sort Earlphia Sells
title Specific microRNA–mRNA Regulatory Network of Colon Cancer Invasion Mediated by Tissue Kallikrein–Related Peptidase 6
title_short Specific microRNA–mRNA Regulatory Network of Colon Cancer Invasion Mediated by Tissue Kallikrein–Related Peptidase 6
title_full Specific microRNA–mRNA Regulatory Network of Colon Cancer Invasion Mediated by Tissue Kallikrein–Related Peptidase 6
title_fullStr Specific microRNA–mRNA Regulatory Network of Colon Cancer Invasion Mediated by Tissue Kallikrein–Related Peptidase 6
title_full_unstemmed Specific microRNA–mRNA Regulatory Network of Colon Cancer Invasion Mediated by Tissue Kallikrein–Related Peptidase 6
title_sort specific microrna–mrna regulatory network of colon cancer invasion mediated by tissue kallikrein–related peptidase 6
publisher Elsevier
series Neoplasia: An International Journal for Oncology Research
issn 1476-5586
1522-8002
publishDate 2017-05-01
description 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.
url http://www.sciencedirect.com/science/article/pii/S1476558616303335
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