The combined restoration of miR-424-5p and miR-142-3p effectively inhibits MCF-7 breast cancer cell line via modulating apoptosis, proliferation, colony formation, cell cycle and autophagy.

BACKGROUND: The combined restoration of tumor-suppressive microRNAs (miRs) has been identified as a promising approach for inhibiting breast cancer development. This study investigated the effect of the combined restoration of miR-424-5p and miR-142-3p on MCF-7 cells and compared the efficacy of the combined therapy with the monotherapies with miR-424-5p and miR-142-3p. METHODS: After transfection of miR-424-5p and miR-142-3p mimics into MCF-7 cells in the combined and separated manner, the proliferation of tumoral cells was assessed by the MTT assay. Also, the apoptosis, autophagy, and cell cycle of the cells were analyzed by flow cytometry. Western blot and qRT-PCR were used to study the expression levels of c-Myc, Bcl-2, Bax, STAT-3, Oct-3, and Beclin-1. RESULTS: Our results have demonstrated that the combined restoration of miR-424-5p and miR-142-3p is more effective in inhibiting tumor proliferation via upregulating Bax and Beclin-1 and downregulating Bcl-2 and c-Myc. Besides, the combined therapy has arrested the cell cycle in the sub-G1 and G2 phases and has suppressed the clonogenicity via downregulating STAT-3 and Oct-3, respectively. CONCLUSION: The combined restoration of miR-424-5p and miR-142-3p is more effective in inhibiting MCF-7 breast cancer development than monotherapies with miR-424-5p and miR-142-3p.

Current perspectives on the dysregulated microRNAs in gastric cancer.

Since gastric cancer (GC) is diagnosed at advanced stages, the survival rate is low in affected people. In this regard, investigating the mechanisms underlying GC development, are so critical. MiRNAs, which are small non coding RNAs, as a post transcriptional repressor, regulate expression of target genes by stimulating breakage or transcription suppression of their targets therefore aberrant expression of miRNAs leading to GC carcinogenesis. In the last decades, there have been various studies approving the pivotal role of miRNAs in various phases of GC development including cancer initiation, proliferation, migration, invasion, metastasis, angiogenesis, apoptosis, and drug resistance. Therefore, the present review aimed at summarizing the dysregulated miRNAs which contribute to various cellular and developmental mechanisms such as, proliferation, apoptosis, invasion, migration, and angiogenesis. Moreover, it provides an overview on novel miRNAs involved in drug resistance and circular miRNAs as cancer biomarkers. Thereafter, it is hoped that the present study will shed more light on diagnostic and prognostic biomarkers of GC, and potential GC treatments based on miRNAs.

The Value of MiR-383, an Intronic MiRNA, as a Diagnostic and Prognostic Biomarker in Intestinal-Type Gastric Cancer.

MicroRNAs, a class of gene expression regulatory non-coding RNAs, participate in the pathogenic mechanisms of gastric cancer which is one of the life-treating cancers. Due to its aberrant expression in some types of human cancer, miR-383 has the value of being investigated in relation to cancer treatment and diagnosis. MiR-383 is placed in intron of SGCZ, a protein-coding gene, which is subject to dysregulation in various diseases. The purpose of the current study was to investigate the contribution of miR-383 to intestinal-type gastric adenocarcinoma tumorigenesis. The expression level of miR-383 was investigated by qRT-PCR in pairs of tumorous and adjacent tumor-free tissues of 40 patients with gastric cancer during endoscopy. Also, the susceptibility of miR-383 as a tumor marker and the relationship between its aberrant expression and clinicopathological features were determined. qRT-PCR data showed that miR-383 was dysregulated during gastric tumorigenesis. MiR-383 was dramatically downregulated up to sevenfold in intestinal-type gastric adenocarcinoma compared with adjacent tumor-free tissues (P < 0.001). Misregulation of miR-383 did not reveal a significant correlation with clinical characteristics. The ROC area of 80% with 76% sensitivity and 84% specificity was determined by P < 0.001. The current study demonstrated downregulation of miR-383 in intestinal-type gastric adenocarcinoma. Downregulation of miR-383 might be used as a potential tumor marker for the diagnosis of gastric cancer or could be a potential target for gene therapy.

The Value of miR-299-5p in Diagnosis and Prognosis of Intestinal-Type Gastric Adenocarcinoma.

MicroRNAs (miRNAs) are a class of non-coding RNAs, containing about 22 nucleotides and having a pivotal function in various cellular processes. The oncogenic and tumor suppressor roles of miRNAs have been identified in cancers especially in gastric cancer, which is one of the most prevalent cancers. MiR-299-5p is located in the imprinted Dlk1-Dio3 region in chromosome 14q32. Aberrant expression of miR-299-5p was determined in solid and blood cancers. The current study was performed to assess the expression pattern of miR-299-5p in intestinal-type gastric adenocarcinoma and compare it with the normal adjacent counterparts. The expression level of miR-299-5p was investigated in forty fresh specimens which were obtained from gastric cancer patients during endoscopy. Moreover, the association of aberrant expression of miR-299-5p and clinicopathological features, as well as the susceptibility of miR-299-5p as a tumor marker, was determined. The result of qRT-PCR revealed the downregulation of miR-299-5p in intestinal-type gastric adenocarcinoma compared with adjacent tumor-free tissues (P < 0.001); this misregulation can be used as a tumor marker. Analysis of miR-299-5p misregulation did not reveal a significant correlation with clinical features. The result obtained from the present study revealed the significant downregulation of miR-299-5p in intestinal-type gastric adenocarcinoma which is consistent with previous studies showing miR-299-5p downregulation in other types of cancers. The data obtained from the current study suggest basic information which can be very helpful for future research in the field of diagnosis and treatment of gastric cancer.

Differential modulation of PI3K/Akt/mTOR activity by EGFR inhibitors: A rationale for co-targeting EGFR and PI3K in cisplatin-resistant HNSCC.

PURPOSE: To find a new strategy to treat cisplatin-resistant head and neck squamous cell carcinoma (HNSCC), we investigated the effects of EGFR inhibitors on the PI3K/Akt/mTOR pathway and determined the efficacy of EGFR inhibitors in combination with PI3K inhibitors to suppress cell proliferation in cisplatin-resistant-HNSCC. METHODS: The cisplatin-resistant HNSCC cell lines were treated with four FDA approved EGFR inhibitors, which included Gefitinb or Erlotinib alone, or in combination with the pan-PI3K inhibitor, BKM120. Phosphorylation and total protein levels of cells were assessed by Western blot analysis. Cell proliferation was examined by MTS assay. Apoptosis was analyzed by flow cytometry. RESULTS: Cisplatin-resistant HNSCC cells were also resistant to EGFR inhibitors. However, a combination of EGFR inhibitors with PI3K inhibitor BKM120 dramatically improved the efficacy of EGFR inhibitors to inhibit cell proliferation and induce apoptosis. Furthermore, treatment with EGFR inhibitors differentially affected the phosphorylation of Akt and mTOR, which included partial inhibition, no inhibition, and induction. A combination of EGFR inhibitors and BKM120 completely blocked phosphorylation of EGFR, Akt, and S6K (an mTOR target). CONCLUSION: Our data provided a rationale for EGFR inhibitors in combination with PI3K inhibitors to treat cisplatin-resistant HNSCC.

MicroRNA-425: A Pivotal Regulator Participating in Tumorigenesis of Human Cancers.

MicroRNAs (miRNAs) are small single-stranded regulatory RNAs that are shown to be dysregulated in a wide array of human cancers. MiRNAs play critical roles in cancer progression and function as either oncogenes or tumor suppressors through modulating various target genes. Therefore, they possess great potential as diagnostic and therapeutic targets for cancer detection and treatment. In particular, recent studies have illustrated that miR-425 is also dysregulated in various human malignancies and plays a fundamental role in cancer initiation and progression. miR-425 has been reported to function as a dual-role miRNA participating in the regulation of cellular processes, including metastasis, invasion, and cell proliferation by modulating multiple signaling pathways, such as TGF-ß, Wnt, and P13K/AKT pathways. Therefore, regarding recent researches showing the high therapeutic potential of miR-425, in this review, we have noted the impact of its dysregulation on signaling pathways and various aspects of tumorigenesis in a variety of human cancers.

MicroRNA -383-5p restrains the proliferation and migration of breast cancer cells and promotes apoptosis via inhibition of PD-L1.

AIMS: MicroRNAs (miRs) play pivotal roles in breast cancer development. The dysregulation of miRs has been associated with PD-L1-mediated immune suppression. This study aimed to examine the effect of transfected miR-383-5p on breast cancer cells and T-cells and its association with clinicopathological features in affected patients. MAIN METHODS: Initially, miR-383-5p and PD-L1 expression levels were investigated in breast cancer tissues. Then, MDA-MB-231 cells were transfected with miR-383-5p mimics to perform analyses. Cell viability was investigated using the MTT assay, and the annexin V/PI staining assay was performed to examine apoptosis induction. Furthermore, the effect of miR-383-5p on cell migration and cell cycle progression was analyzed using the wound-healing assay and flow cytometry, respectively. Gene and protein expressions were studied using qRT-PCR and western blotting. Finally, the effect of miR-383-5p on T-cells, which were co-cultured with cancer cells, was investigated. KEY FINDINGS: Compared to non-malignant tissues, PD-L1 was up-regulated, and miR-383-5p expression was downregulated in breast cancer tissues. Moreover, miR-383-5p reduced breast cancer cell viability via inducing apoptosis and modulating the expression of apoptosis-related genes. Besides, miR-383-5p could inhibit the migration of breast cancer cells via down-regulating metastasis-related genes. Besides, transfected miR-383-5p induced the secretion of pro-inflammatory cytokines from T-cells. Furthermore, the results showed that miR-383-5p might exert its tumor-suppressive effect via inhibiting the PI3K/AKT/mTOR pathway. The inhibitory effect of transfected miR-383-5p on the PI3K/AKT/mTOR pathway might be the underlying mechanism for inhibiting tumoral PD-L1 expression. SIGNIFICANCE: Overall, miR-383-5p can be a promising therapeutic agent for treating breast cancer.

The combined therapy of miR-383-5p restoration and paclitaxel for treating MDA-MB-231 breast cancer.

The deregulation of microRNAs (miRs) has been identified in tumor development. Indeed, the restoration of tumor-suppressive miRs has been associated with inhibited tumor development in various cancers. Herein, we aimed to evaluate the impact of combined miR-383-5p restoration, as a tumor-suppressive miR, with taxol therapy in suppressing MDA-MB-231 breast cancer development. MDA-MB-231 cell line was restored with miR-383-5p and treated with paclitaxel both in combined and separate manners. The MTT experiment was carried out to measure the cytotoxicity of the therapeutic approaches on the tumoral cells. Besides, flow cytometry was conducted to assess apoptosis and cell cycle status following the treatments. Furthermore, the expression levels of critical factors contributed to tumor proliferation, migration, apoptosis were investigated via the qRT-PCR and western blotting techniques. The outcomes pointed out that the miR-383-5p might substantially enhance the chemosensitivity of MDA-MB-231 to taxol. Besides, miR-383-5p restoration and the combined therapy of miR-383-5p restoration with paclitaxel could remarkably increase apoptosis, decrease cell viability, arrest the cell cycle, inhibit clonogenicity, suppress tumor migration, suppress the PI3K/Akt signaling pathway, and down-regulate PD-L1 expression of BC cells. The restoration of miR-383-5p can enhance the chemosensitivity of MDA-MB-231 cells to taxol. Despite the anti-tumoral effects of miR-383-5p restoration on MDA-MB-231 breast cancer development, the combined therapy of miR-383-5p restoration with paclitaxel can be more effective in repressing MDA-MB-231 breast cancer development.

Importance of miR-299-5p in colorectal cancer.

BACKGROUND: MicroRNAs (miRNAs) are effective regulators of gene expression that play a pivotal role in the pathogenesis of colorectal cancer (CRC) and various other cancers. The high prevalence of aberrant miRNA expression in CRC suggests that they can be used as biomarkers and anticancer molecules for therapeutic purposes. There is evidence that microRNA-299-5p (miR-299-5p) is associated with vital cell processes (e.g. epithelial-mesenchymal transition, proliferation, and tumorigenicity) and its improper expression with tumorigenesis in many types of human cancer. This prospective study investigated the contribution of miR-299-5p to CRC tumorigenesis. METHODS: The real-time reverse transcription-polymerase chain reaction was used to examine miR-299-5p expression levels prospectively in 40 sample pairs of CRC tissue and adjacent noncancerous tissue (>2 cm from cancer tissue). The ability of miR-299-5p to function as a tumor marker was also examined. RESULTS: The expression levels of miR-299-5p were significantly downregulated in the group of CRC samples compared with matched noncancerous tissue samples. No significant relationship was found between miR-299-5p expression levels and clinicopathological features. Receiver operating characteristic analysis gave an area under the curve of 71% for miR-299-5p with 68% sensitivity and 78% specificity (P=0.001). CONCLUSION: The miRNA miR-299-5p may be considered as a tumor marker in CRC and could be of assistance as a potential predictive biomarker in the diagnosis of this cancer.

Diagnostic and Prognostic Value of miR-1287 in Colorectal Cancer.

INTRODUCTION: MicroRNAs are non-coding RNAs that regulate the gene expression at post-transcriptional level. This futuristic study characterized the contribution of miR-1287 to the colorectal cancer (CRC) tumorigenesis. METHODS: The real-time reverse transcription-polymerase chain reaction was used to examine miR-1287 expression levels, prospectively in 40 pairs of CRC tissue samples and adjacent noncancerous tissues (>2 cm from cancer tissue). RESULTS: No significant relationship was found between miR-1287 expression levels and clinicopathological features. Showing significant changes overall, MiR-1287 was significantly upregulated in the group of CRC samples compared with matched noncancerous tissue samples. A receiver operating characteristic (ROC) curve also showed ROC area (AROC) of 34 % with 1.0 and 0.02 sensitivity and specificity, respectively. Expression of miR-1287, with a value of 0.34, P value = 1.98, and P > 0.05, revealed that this microRNA has a low sensitivity and specificity to be regarded as a tumor marker. CONCLUSIONS: With regard to recent increased rate of CRC in the world, the present study may be a contribution, though very small, in the diagnosis and consequently in the treatment of CRC patients.