A claudin-based molecular signature identifies high-risk, chemoresistant colorectal cancer patients Journal Article
| Authors: | Gowrikumar, S.; Primeaux, M.; Pravoverov, K.; Wu, C.; Szeglin, B. C.; Sauvé, C. E. G.; Thapa, I.; Bastola, D.; Chen, X. S.; Smith, J. J.; Singh, A. B.; Dhawan, P. |
| Article Title: | A claudin-based molecular signature identifies high-risk, chemoresistant colorectal cancer patients |
| Abstract: | Identifying molecular characteristics that are associated with aggressive cancer phenotypes through gene expression profiling can help predict treatment responses and clinical outcomes. Claudins are deregulated in colorectal cancer (CRC). In CRC, increased claudin-1 expression results in epithelial-to-mesenchymal transition and metastasis, while claudin-7 functions as a tumor suppressor. In this study, we have developed a molecular signature based on claudin-1 and claudin-7 associated with poor patient survival and chemoresistance. This signature was validated using an integrated approach including publicly available datasets and CRC samples from patients who either responded or did not respond to standard-of-care treatment, CRC cell lines, and patient-derived rectal and colon tumoroids. Transcriptomic analysis from a patient dataset initially yielded 23 genes that were differentially expressed along with higher claudin-1 and decreased claudin-7. From this analysis, we selected a claudins-associated molecular signature including PIK3CA, SLC6A6, TMEM43, and ASAP-1 based on their importance in CRC. The upregulation of these genes and their protein products was validated using multiple CRC patient datasets, in vitro chemoresistant cell lines, and patient-derived tumoroid models. Additionally, blocking these genes improved 5-FU sensitivity in chemoresistant CRC cells. Our findings propose a new claudin-based molecular signature that associates with poor prognosis as well as characteristics of treatment-resistant CRC including chemoresistance, metastasis, and relapse. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. |
| Keywords: | immunohistochemistry; controlled study; human tissue; protein expression; unclassified drug; human cell; fluorouracil; nonhuman; cancer staging; colorectal cancer; mouse; phenotype; animal tissue; cell viability; metastasis; gene expression; small interfering rna; transcriptomics; uvomorulin; assay; high risk patient; alpha smooth muscle actin; membrane protein; western blotting; down regulation; real time polymerase chain reaction; upregulation; gene silencing; experimental neoplasm; cd133 antigen; epithelial cell adhesion molecule; oxaliplatin; hermes antigen; transcription factor nanog; rna extraction; receiver operating characteristic; vimentin; recurrence free survival; epithelial mesenchymal transition; chemoresistance; peptides and proteins; claudin-7; molecular signature; laser microscopy; gene knockdown; claudin; phosphatidylinositol 4,5 bisphosphate 3 kinase; human; article; claudin 7; crc; hierarchical clustering; immunofluorescence assay; ic50; claudin 1; claudin-1; membrane protein 43; taurine transporter; dld-1 cell line; ht-29 cell line; sphere formation assay; sw480 cell line |
| Journal Title: | Cells |
| Volume: | 10 |
| Issue: | 9 |
| ISSN: | 2073-4409 |
| Publisher: | MDPI |
| Date Published: | 2021-09-01 |
| Start Page: | 2211 |
| Language: | English |
| DOI: | 10.3390/cells10092211 |
| PUBMED: | 34571860 |
| PROVIDER: | scopus |
| PMCID: | PMC8466455 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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