Abstract
ObjectiveIncreasing evidence has revealed that mechanical stress and elevated mechanical signals promote malignant tumor transformation and metastasis. This study aimed to explore the function of the mechanically activated ion-channel Piezo1 in the colon cancer metastasis and its potential regulatory mechanism.MethodsFirst, we examined the expression levels of Piezo1 and mitochondrial calcium uniporter (MCU) both in colon cancer tissues and assessed the prognostic value of Piezo1 and MCU in a colon cancer cohort (n = 110). Second, functional assays were performed to investigate the effects of Piezo1 and MCU on colon cancer cell migration, invasion, and mitochondrial membrane potential. Third, we analyzed the expression of Piezo1, MCU, and HIF-1α by overexpressing/silencing each other’s expression.ResultsWe found that Piezo1 was up-regulated and MCU was down-regulated in colon cancer tissues. Piezo1 and MCU were both correlated with poor prognosis of patients with colon cancer. Overexpressing Piezo1 and silencing MCU could promote colon cancer cell migration and metastasis, reduce mitochondrial membrane potential, and promote each other’s expression. We also found that HIF-1α was up-regulated in colon cancer tissues. Additionally, silencing Piezo1 inhibited the expression of HIF-1α and VEGF, which was contrary to MCU silencing. Intriguingly, Piezo1-overexpressing cells did not regain their migration behaviors when HIF-1α expression was inhibited, which was accompanied with the re-expression of MCU and VEGF.ConclusionIn our study, Piezo1 is involved in colon cancer cell metastasis. Furthermore, our findings indicated a possible Piezo1-MCU-HIF-1α-VEGF axis, which still need further exploration.
Highlights
Despite improvements and advances in diagnostic and therapeutic strategies, colon cancer remains the leading cause of cancer-related deaths worldwide (Siegel et al 2018; Chaffer and Weinberg 2011)
We found that Piezo1 expression was up-regulated in colon cancer tissues
With regard to the mechanism by which Piezo1 is up-regulated in colon cancer, we found that Piezo1 mRNA was significantly increased
Summary
Despite improvements and advances in diagnostic and therapeutic strategies, colon cancer remains the leading cause of cancer-related deaths worldwide (Siegel et al 2018; Chaffer and Weinberg 2011). The identification of key molecular targets is of significant value for the diagnosis and treatment of patients with metastatic colon cancer. We analyzed a novel mechanically activated ion-channel Piezo, as a potential molecular target for metastatic colon cancer. Tumor cell mobility is affected by a variety of signaling cascades, including ion channels and transporters (Schwab and Stock 2014). Sensitive calcium-permeable ion channels are mainly involved in the process of cell movement (Chaffer and Weinberg 2011). Sensitive channels can regulate calciumdependent signaling cascades associated with tumor cell migration by promoting local calcium influx (Maroto and Hamill 2007). HIF-1α, a Ca2+-sensitive factor, has been confirmed to be involved in tumor cell metastasis by promoting EMT (Chen et al 2017). We hypothesized Piezo1-MCUHIF-1α-VEGF axis, a potential regulatory mechanism in colon cancer metastasis
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