miRNA-148a Enhances the Treatment Response of Patients with Rectal Cancer to Chemoradiation and Promotes Apoptosis by Directly Targeting c-Met

Abstract

Patients with locally advanced rectal cancer (LARC) who achieve a pathological complete response (pCR) to neoadjuvant chemoradiotherapy (NACRT) have an excellent prognosis, but only approximately 30% of patients achieve pCR. Therefore, identifying predictors of pCR is imperative. We employed a microRNA (miRNA) microarray to compare the miRNA profiles of patients with LARC who achieved pCR (pCR group, n = 5) with those who did not (non-pCR group, n = 5). The validation set confirmed that miRNA-148a was overexpressed in the pCR group (n = 11) compared with the non-pCR group (n = 40). Cell proliferation and clonogenic assays revealed that miRNA-148a overexpression radio-sensitized cancer cells and inhibited cellular proliferation, before and after irradiation (p < 0.01). Apoptosis assays demonstrated that miRNA-148a enhanced apoptosis before and after irradiation. Reporter assays revealed that c-Met was the direct target gene of miRNA-148a. An in vivo study indicated that miRNA-148a enhanced the irradiation-induced suppression of xenograft tumor growth (p < 0.01). miRNA-148a may be a biomarker of pCR following NACRT and can promote apoptosis and inhibit proliferation in CRC cells by directly targeting c-Met in vitro and enhancing tumor response to irradiation in vivo.

MicroRNA-148a induces apoptosis and prevents angiogenesis with bevacizumab in colon cancer through direct inhibition of ROCK1/c-Met via HIF-1α under hypoxia

“…We previously demonstrated that miR-148a suppressed VEGF through the downregulation of the pERK/HIF-1α/VEGF pathway, thereby inhibiting angiogenesis [ 7 ]. The overexpression of miR-148a assisted apoptosis and curbed proliferation by directly targeting c-Met in vitro and improved the tumor response to irradiation in vivo [ 19 ]. Nersisyan et al reported that the ITGA5 gene and PRNP gene were upregulated in Caco-2 cells exposed to chemical hypoxia.…”

“…A study demonstrated that miR-148a suppresses the epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma by targeting c-Met [17]. We have previously observed that miR-148a inhibits tumorigenesis and reduces the likelihood of early CRC recurrence [18], improves the response to chemoradiation and increases apoptosis by directly targeting c-Met in patients with rectal cancer [19], indirectly inhibits VEGF secretion by targeting HIF-1α [7], and exhibits the apoptotic effect of alterations of myeloid cell leukemia 1 (Mcl-1) expression on CRC [20]. Xu et al demonstrated in 2018 that chemokine CC ligand 19 (CCL19) inhibits CRC angiogenesis by promoting miR-206 and thereby inhibiting the Met/ERK/HIF-1α/VEGF-A pathway [21].…”

Functional effects of drugs and toxins interacting with NaV1.4

“…Other antiepileptics, such as lacosamide and rufinamide, can also reduce myotonia in isolated human and rat skeletal muscles, but they have different inhibitory concentrations ( Skov et al, 2017 ). In 2021, a cannabinoid from the cannabis plant, cannabidiol (CBD), was reported to relieve myotonia caused by sodium channelopathy, especially when the channel is in its slow inactivation state, owing to its high binding affinity for Na V 1.4 channels ( Huang et al, 2021 ). Ghovanloo et al (2021) also studied the localization of CBD in the membrane using MD simulation and nuclear magnetic resonance and found that CBD could reduce the excitability of the Na V 1.4 P1158S mutant (associated with NDM and PP).…”