TRPM4 is highly expressed in human colorectal tumor buds and contributes to proliferation, cell cycle, and invasion of colorectal cancer cells.

Kappel, Sven; Stoklosa, Paulina; Hauert, Barbara; Ross-Kaschitza, Daniela; Borgström, Anna; Baur, Roland; Galván, José A.; Zlobec, Inti; Peinelt, Christine (2019). TRPM4 is highly expressed in human colorectal tumor buds and contributes to proliferation, cell cycle, and invasion of colorectal cancer cells. Molecular oncology, 13(11), pp. 2393-2405. FEBS Press 10.1002/1878-0261.12566

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Transient receptor potential melastatin-4 channel (TRPM4) dysregulation contributes to heart conditions, immune diseases, and cervical and prostate cancer. Up to now, the involvement of TRPM4 in colorectal cancer (CRC) pathophysiology remains unknown. Here, we investigated tumor tissue microarrays from 379 CRC patients and analyzed TRPM4 protein expression, tumor characteristics, and clinical outcome. High TRPM4 protein expression was associated with unfavorable tumor features characteristic for epithelial-mesenchymal transition and infiltrative growth patterns, that is, a high number of tumor buds and a low percentage in tumor border configuration. Compared to CRC cells representing early cancer stages, TRPM4 protein expression was the highest in cells representing late-stage metastatic cancer. Investigation of CRC cell line HCT116 and five CRISPR/cas9 TRPM4 knockout clones demonstrated that TRPM4 exhibited large Na+ current densities (~ 60 pA/pF). In addition, CRISPR/cas9 TRPM4 knockout clones showed a tendency toward decreased migration and invasion, cell viability, and proliferation and exhibited a shift in cell cycle when compared to HCT116. Stable overexpression of TRPM4 (TRPM4 wild-type) in two CRISPR/cas9 TRPM4 knockout clones rescued the decrease in cell viability and cell cycle shift. Stable overexpression of a nonconducting, dominant-negative TRPM4 mutant (TRPM4 D894A) did not rescue the decrease in viability or cell cycle shift. Taken together, these findings pointed to TRPM4 ion channel conductivity as the underlying mechanism for decreased viability and cell cycle shift in the TRPM4 knockout clones. Together with previous findings, our present data suggest that TRPM4 plays a versatile role in cancer cell proliferation, cell cycle, and invasion.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Translational Research Unit

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Kappel, Sven; Stoklosa, Paulina Agnieszka; Hauert, Barbara; Ross, Daniela; Borgström, Anna; Baur, Roland; Galván Hernández, José Alberto; Zlobec, Inti and Peinelt, Christine

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1878-0261

Publisher:

FEBS Press

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

26 Sep 2019 15:13

Last Modified:

07 Nov 2019 10:06

Publisher DOI:

10.1002/1878-0261.12566

PubMed ID:

31441200

Uncontrolled Keywords:

CRISPR/cas9 TRPM4 cancer hallmarks cell cycle analysis colorectal cancer tumor buds

BORIS DOI:

10.7892/boris.133496

URI:

https://boris.unibe.ch/id/eprint/133496

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