Abstract
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.
Highlights
In 2018, 1.8 million cases of colorectal cancer (CRC) were registered worldwide and ~ 881 000 patients died of CRC (World Health Organization, 2018)
Analysis of tumor features from 379 patients revealed that high levels of Transient receptor potential melastatin-4 channel (TRPM4) protein were related to aggressive tumor features, including high numbers of tumor buds—which is a sign of epithelial–mesenchymal transition (EMT), metastasis, and more aggressive infiltrative growth patterns in CRC (Fig. 1) (Georges et al, 2018; Karamitopoulou et al, 2015; Koelzer et al, 2016)
The imbalance of mRNA versus protein level in Colo205 may reflect that while TRPM4 mRNA expression in CRC is decreased (Sozucan et al, 2015), we find high TRPM4 protein expression correlated with tumor budding and tumor border configuration (TBC)
Summary
In 2018, 1.8 million cases of colorectal cancer (CRC) were registered worldwide and ~ 881 000 patients died of CRC (World Health Organization, 2018). As in other types of cancer, driver mutations in several key signaling pathways promote CRC pathogenicity. Alterations in the PI3K, WNT, and KRAS. Abbreviations CD, current density; CRC, colorectal cancer; TBC, tumor border configuration; TRPM4, transient receptor potential melastatin-4 channel. Molecular Oncology 13 (2019) 2393–2405 a 2019 The Authors.
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