KCNE4 expression is correlated with the pathological characteristics of colorectal cancer patients and associated with the radioresistance of cancer cells

Colorectal cancer (CRC) is a common gastrointestinal malignancy globally [1]. Currently, patients with CRC, especially for those with rectal cancer, are commonly treated with a combination of surgical resection and chemoradiotherapy. In many patients, preoperative chemoradiotherapy (neoadjuvant therapy) can help reduce tumor size, improve the rate of radical resection, and reduce the possibility of local recurrence [2]. Nonetheless, some patients are resistant to radiotherapy and thus fail to benefit from preoperative radiotherapy, even leading to tumor progression [3]. Therefore, exploring the molecular mechanisms that affect the radioresistance of rectal cancer cells contributes to developing new therapies, which is highly important for improving the prognosis of CRC patients, especially for the rectal cancer patients who receive radiotherapy.

There is mounting evidence that there are plenty of dysregulated genes in CRC tumorigenesis, some of which are associated with the radioresistance of CRC cells. For instance, proteasome activator subunit 3 (PSME3) is markedly upregulated in CRC tissues and cells, and high PSME3 expression is strongly linked to CRC patients’ poor progression-free survival and overall survival; it is further found that PSME3 knockdown down-regulates cyclinB1 and CDK1 to induce cell cycle arrest, thus elevating the radiosensitivity of CRC cells [4]. B7-H3 expression is markedly elevated in CRC cells following radiation irradiation, and B7-H3 overexpression facilitates colony formation and viability of CRC cells after radiation irradiation and represses cell cycle arrest and apoptosis [5]. Potassium voltage-gated channel subfamily E regulatory subunit (KCNE) family members are a group of small, single transmembrane domain proteins [6]. As a member of the KCNE family, KCNE4 has been reported to have a significant effect on the ionic equilibrium of cells [7]. In CRC, KCNE4 expression is up-regulated and remarkably related to immune cell infiltration level and short patients' survival [8]. Nevertheless, the specific role and regulatory mechanism of KCNE4 in radioresistance of rectal cancer cells remain unclear.

Additionally, the phosphatidylinositol‑4,5–bisphosphate 3–kinase/protein kinase B (PI3K/AKT) signaling pathway is a classical pathway involved in cancer biology, which is associated with tumor cell growth, death, and metastasis [9]. It is reported that in CRC, PI3K/AKT signal pathway is frequently activated in radioresistant cells [10]. In this study, radiation-resistant CRC cell lines (HCT116/IR and HT29/IR) were constructed by irradiating CRC cells with ionizing radiation (IR), and the effects of KCNE4 on the viability and apoptosis of HCT116/IR and HT29/IR cells were examined. Furthermore, the downstream mechanisms of KCNE4 in modulating the phenotypes of HCT116/IR and HT29/IR cells were further identified.

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