TRIP13 promotes metastasis of colorectal cancer regardless of p53 and microsatellite instability status

Autor: Michael Behring, Hyung-Gyoon Kim, Sooryanarayana Varambally, Balabhadrapatruni V. S. K. Chakravarthi, Pran K. Datta, Prachi Bajpai, Amr Elkholy, Sameer Al Diffalha, Sumit Agarwal, Martin J. Heslin, Darshan S. Chandrashekar, Nirzari Gupta, Upender Manne
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
Cancer Research
Colorectal cancer
Cell Cycle Proteins
Mice
SCID
Metastasis
0302 clinical medicine
Mice
Inbred NOD
KLK7
Neoplasm Metastasis
Research Articles
Wnt signaling pathway
General Medicine
Middle Aged
ErbB Receptors
Gene Expression Regulation
Neoplastic
Phenotype
Oncology
WNT/β‐catenin
030220 oncology & carcinogenesis
Molecular Medicine
Female
Microsatellite Instability
Colorectal Neoplasms
Protein Binding
Signal Transduction
Research Article
Adenoma
TRIP13
EGFR
colorectal cancer
Biology
03 medical and health sciences
Cell Line
Tumor
Genetics
Carcinoma
medicine
Animals
Humans
metastasis
Receptor
Fibroblast Growth Factor
Type 4
neoplasms
Aged
Neoplasm Staging
Base Sequence
Microsatellite instability
medicine.disease
digestive system diseases
MicroRNAs
030104 developmental biology
Exoribonucleases
FGFR4
Cancer research
ATPases Associated with Diverse Cellular Activities
Tumor Suppressor Protein p53
Proto-Oncogene Proteins c-akt
Zdroj: Molecular Oncology
ISSN: 1878-0261
1574-7891
DOI: 10.1002/1878-0261.12821
Popis: This study demonstrates overexpression of TRIP13 in colorectal cancers is independent of patient's gender, age, race/ethnicity, pathologic stage (primary and liver metastatic lesions), and p53 and microsatellite instability status. Furthermore, it establishes role of TRIP13 in colorectal cancer metastasis and identifies COL6A3, TREM2, SHC3, and KLK7 as its downstream targets. Additionally, TRIP13 activates EGFR‐AKT pathway via its interaction with FGFR4.
Overexpression of TRIP13, a member of the AAA‐ATPase family, is linked with various cancers, but its role in metastasis is unknown in colorectal cancer (CRC). In the current study, we investigated the role TRIP13 in experimental metastasis and its involvement in regulation of WNT/β‐catenin and EGFR signaling pathways. Evaluation of formalin‐fixed paraffin‐embedded (FFPE) and frozen tissues of adenomas and CRCs, along with their corresponding normal samples, showed that TRIP13 was gradually increased in its phenotypic expression from adenoma to carcinoma and that its overexpression in CRCs was independent of patient's gender, age, race/ethnicity, pathologic stage, and p53 and microsatellite instability (MSI) status. Moreover, liver metastases of CRCs showed TRIP13 overexpression as compared to matched adjacent liver tissues, indicating the biological relevance of TRIP13 in CRC progression and metastasis. TRIP13 knockdown impeded colony formation, invasion, motility, and spheroid‐forming capacity of CRC cells irrespective of their p53 and MSI status. Furthermore, xenograft studies demonstrated high expression of TRIP13 contributed to tumor growth and metastasis. Depletion of TRIP13 in CRC cells decreased metastasis and it was independent of the p53 and MSI status. Furthermore, TRIP13 interacted with a tyrosine kinase, FGFR4; this interaction could be essential for activation of the EGFR‐AKT pathway. In addition, we demonstrated the involvement of TRIP13 in the Wnt signaling pathway and in the epithelial–mesenchymal transition. Cell‐based assays revealed that miR‐192 and PNPT1 regulate TRIP13 expression in CRC. Additionally, RNA sequencing of CRC cells with TRIP13 knockdown identified COL6A3, TREM2, SHC3, and KLK7 as downstream targets that may have functional relevance in TRIP13‐mediated tumor growth and metastasis. In summary, our results demonstrated that TRIP13 promotes tumor growth and metastasis regardless of p53 and MSI status, and indicated that it is a target for therapy of CRC.
Databáze: OpenAIRE
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