miR-365a-3p regulates ADAM10-JAK-STAT signaling to suppress the growth and metastasis of colorectal cancer cells

Abstract

Purpose: MicroRNAs (miRNAs) are key regulators of the growth and development of a wide range of cancer types such as colorectal cancer (CRC). A number of previously studies have observed that the levels of miR-365a-3p expression are dysregulated in many cancers, but the specific role of this miRNA in CRC and its association with patient prognosis remains unclear. Methods: The expression of miR-365a-3p in CRC tissues and cell lines was detected by Real-time Quantitative polymerase chain reaction (RT-qPCR), while the relationship between miR-365a-3p expression and clinicopathological characteristics was further analyzed. After increasing the expression of miR-365a-3p by plasmid transfection in CRC cells, we further investigated the cell proliferation, invasion and migration by cell counting kit-8 (CCK-8), and Transwell assays. Epithelial-mesenchymal transition (EMT) pathway was also measured by western blotting. In addition, the relationship among miR-365a-3p, ADAM10 and JAK in CRC, was explored by luciferase reporter assay. Results: In the present study, we determined that CRC cells and clinical samples exhibited decreased miR-365a-3p expression, and this was associated with larger tumor size, lymph node metastasis, and local invasion. Patients with lower expression of miR-365a-3p had significantly decreased recurrence-free survival (RFS) and overall survival (OS) relative to those with higher levels of this miRNA. In a multivariate analysis, we confirmed that reduced miR-365a-3p levels were independently predictive of poorer CRC patient outcomes. In a functional study, we determined that elevated miR-365a-3p expression inhibited the ability of CRC cells to proliferate and metastasize in vitro and in vivo. We further identified ADAM10 as a direct miR-365a-3p target, resulting in the suppression of ADAM10 expression in cells expressing this miRNA and ADAM10 levels were in turn closely linked to JAK/STAT signaling. Conclusion: Our study suggested the ability of miR-365a-3p to inhibit the progression of CRC at least in part via suppressing ADAM10 expression and associated JAK/STAT signaling, thus identifying this signaling axis as a possible prognostic and therapeutic target in CRC.

Melatonin inhibits proliferation and viability and promotes apoptosis in colorectal cancer cells via upregulation of the microRNA-34a/449a cluster

“…HCT116 cell viability and apoptosis were significantly changed compared with other cell lines. All of the aforementioned miRNAs have been reported to be associated with CRC cell proliferation and apoptosis (36,38,56,57). The results of the present study demonstrated that only miR-34a and miR-449a expression levels were significantly altered by melatonin treatment compared with the control group (Fig.…”

JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy

“…Various regulatory agencies now uphold JAK inhibitors (JAKinibs) for the treatment of immune-mediated diseases [ 79 ]. Aberrant activation of STAT3 is a characteristic feature of abnormal cellular differentiation and proliferation [ 80 ]. The FERM and SH 2 like domains of JAKs regulate the kinase activity, whereas gene transcription is modulated by STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6 [ 81 ].…”

<p>Long Non-Coding RNA C1QTNF1 Antisense RNA 1 Upregulates Hexokinase 2 by Sponging microRNA-484 to Promote the Malignancy of Colorectal Cancer</p>

“…21 Changes in miRNA expression in CRC have been widely reported, and their abnormal expression has been notably correlated with CRC tumorigenesis. [22][23][24] Recently, the competitive endogenous RNA (ceRNA) hypothesis was proposed and is now widely accepted. 25,26 lncRNAs are a type of ceRNA that work as molecular sponges for miRNAs, regulating target mRNAs at the posttranscriptional level.…”