Combination of SIX4-siRNA and temozolomide inhibits the growth and migration of A-172 glioblastoma cancer cells.

Glioblastoma is one of the most common and invasive types of primary brain malignancies in adults, accounting for 45.5% of malignancies. Its annual prevalence is low compared to other cancers. The survival rate of this disease is about 14 months after diagnosis. Temozolomide (TMZ) is a common chemotherapy drug used to treatment of glioblastoma, but drug resistance against this drug is an important barrier to successful treatment of this cancer. Today, siRNAs play a significant role in cancer treatment. SIX4 is a transcriptional regulatory molecule that can act as a transcriptional suppressor and an activator in target genes involved in differentiation, migration, and cell survival processes. The aim of this study was to evaluate the effect of SIX4-siRNA on A-172 glioblastoma cells, its role as a tumor suppressor, and its combination with TMZ. We studied the cytotoxic effect of the SIX4-siRNA and TMZ on A-172 cells using the MTT assay investigated their effect on apoptosis and cell cycle of A-172 cells used wound healing assays to assess their effect on cell migration. Finally, we used qRT-PCR to study the mRNA expression levels of genes involved in apoptosis and migration of tumoral cells after treatments. Based on our results, silencing SIX4-siRNA expression reduced the cell viability of A-172 cells and sensitize these cells to TMZ. Furthermore, we observed an increase in apoptosis and cell cycle arrest, and a decrease in migration. Bax and caspase-9 overexpression and BCL2 and MMP9 downregulation were detected in the combination of SIX4-siRNA and TMZ. According to our results, the combination of SIX4-siRNA and TMZ can be a very useful strategy for successful glioblastoma treatment.

Identification of Common and Distinct Pathways in Inflammatory Bowel Disease and Colorectal Cancer: A Hypothesis Based on Weighted Gene Co-Expression Network Analysis.

Patients with inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, are at higher risk to develop colorectal cancer (CRC). However, the underlying mechanisms of this predisposition remain elusive. We performed in-depth comparative computational analyses to gain new insights, including weighted gene co-expression network analysis (WGCNA) and gene ontology and pathway enrichment analyses, using gene expression datasets from IBD and CRC patients. When individually comparing IBD and CRC to normal control samples, we identified clusters of highly correlated genes, differentially expressed genes, and module-trait associations specific for each disease. When comparing IBD to CRC, we identified common hub genes and commonly enriched pathways. Most notably, IBD and CRC share significantly increased expression of five genes (MMP10, LCN2, REG1A, REG3A, and DUOX2), enriched inflammatory and neutrophil activation pathways and, most notably, highly significant enrichment of IL-4 and IL-13 signaling. Thus, our work expands our knowledge about the intricate relationship between IBD and CRC development and provides new rationales for developing novel therapeutic strategies.

miR-200c increases the sensitivity of breast cancer cells to Doxorubicin through downregulating MDR1 gene.

BACKGROUND: Breast cancer (BC) has been known as the most common type of cancer worldwide and resulted in death among women. BC is usually resistant to standard therapies that are significant problems in managing BC patients. miR-200c belongs to the miRNA family, which is considered as a tumor suppressor with reduced expression levels in various kinds of cancer like BC. Increased expression of miR-200c has been reported as a potent inhibitor of drug resistance and tumor advancement. The purpose of this paper is to examine the outcome of miR-200c restoring on enhancing the BC cells' sensitivity to Doxorubicin through downregulating the MDR1 expression. METHODS: Initially, MDA-MB-231 cells were transfected with miR-200c to perform functional analyses. After that, MTT assay was performed to investigate the viability of the cell. Finally, qRT-PCR was used to assess gene expression. RESULTS: According to the results, the miR-200c expression was downregulated in BC cells compared to control. Moreover, the cell viability was reduced in transfected cells via regulation in gene expression associated with apoptosis. Furthermore, miR-200c could increase the BC cells' sensitivity to Doxorubicin by reducing the MDR1 gene expression. CONCLUSION: Hence, this study's findings recommend that miR-200c can consider as a method of therapy for the treatment of BC.

Exploiting systems biology to investigate the gene modules and drugs in ovarian cancer: A hypothesis based on the weighted gene co-expression network analysis.

BACKGROUND: Ovarian cancer (OC) is one of the worrisome gynecological cancers worldwide. Given its considerable mortality rate, it is necessary to investigate its oncogenesis. METHODS: In this study, we used systems biology approaches to describe the key gene modules, hub genes, and regulatory drugs associated with serous OC as the novel biomarkers using weighted gene co-expression network analysis (WGCNA). FINDINGS: Our findings have demonstrated that the blue module genes (r = 0.8, p-value = 1e-16) are involved in OC progression. Based on gene enrichment analysis, the genes in this module are frequently involved in biological processes such as the Cyclic adenosine monophosphate (cAMP) signaling pathway and the cellular response to transforming growth factor-beta stimulation. The co-expression network has been built using the correlated module's top hub genes, which are ADORA1, ANO9, CD24P4, CLDN3, CLDN7, ELF3, KLHL14, PRSS8, RASAL1, RIPK4, SERINC2, and WNT7A. Finally, a drug-target network has been built to show the interaction of the FDA-approved drugs with hub genes. CONCLUSIONS: Our results have discovered that ADORA1, ANO9, SERINC2, and KLHL14 are hub genes associated with serous OC. These genes can be considered as novel candidate target genes for treating OC.

Cytotoxic T-Lymphocyte Antigen-4 in Colorectal Cancer: Another Therapeutic Side of Capecitabine.

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory immune checkpoint that can be expressed in tumor-infiltrating lymphocytes and colorectal cancer (CRC) cells. This immune checkpoint can attenuate anti-tumoral immune responses and facilitate tumor growth and metastasis. Although capecitabine is an effective chemotherapeutic agent for treating CRC, its effect on the tumoral CTLA-4 expression remains unclear. In the current research, we applied the GSE110224 and GSE25070 datasets to characterize CTLA-4 expression in CRC patients. Then, we analyzed CTLA-4 expression in CRC samples, HT-29, HCT-166, and SW480 cell lines using real-time PCR. Our bioinformatic results have highlighted the overexpression of CTLA-4 in the CRC tissues compared to the adjacent non-tumoral tissues. Our in vitro studies have indicated that SW480 cells can substantially overexpress CTLA-4 compared to HT-29 and HCT 116 cells. In addition, capecitabine can remarkably downregulate the expression of CTLA-4 in SW480 cells. Collectively, capecitabine can inhibit the expression of CTLA-4 in CRC cells and might bridge the immunotherapy approaches with chemotherapy.

Pancreatic Cancer Signaling Pathways, Genetic Alterations, and Tumor Microenvironment: The Barriers Affecting the Method of Treatment.

Genetic alterations, especially the K-Ras mutation, carry the heaviest burden in the progression of pancreatic precursor lesions into pancreatic ductal adenocarcinoma (PDAC). The tumor microenvironment is one of the challenges that hinder the therapeutic approaches from functioning sufficiently and leads to the immune evasion of pancreatic malignant cells. Mastering the mechanisms of these two hallmarks of PDAC can help us in dealing with the obstacles in the way of treatment. In this review, we have analyzed the signaling pathways involved in PDAC development and the immune system's role in pancreatic cancer and immune checkpoint inhibition as next-generation therapeutic strategy. The direct targeting of the involved signaling molecules and the immune checkpoint molecules, along with a combination with conventional therapies, have reached the most promising results in pancreatic cancer treatment.

Envisioning the immune system to determine its role in pancreatic ductal adenocarcinoma: Culprit or victim?

Pancreatic ductal adenocarcinoma has a poor 5-year survival rate that makes it one of the most fatal human malignancies. Unfortunately, despite the serious improvement in the survival of most cancers, there has been a minor advance in pancreatic cancer (PC). Major advances in PC treatment have been assessed over the bygone twenty-year time span, yet some complications make the survival of the patients shorter. Getting to know the PC tumor microenvironment (TME) and the immunosuppression that happens during the pathogenesis of this malignancy could be a great help to understand the nature of the immune system and find better treatment modalities based on it. Although many immune cells are present in PC, immunosuppression of the TME leads to severe immune dysfunction in the patients, therefore immune effectors fail to do their functions. Lately, immunotherapy has been presented as one of the promising treatment strategies for different malignancies including hepatocellular carcinoma, melanoma, non-small cell lung cancer, and kidney cancer. In PC, there has been shown promising results centered around the TME, immune checkpoint inhibitors, cancer vaccines, and other approaches especially when used as combinational therapy. Here we dig a little deeper into the role of the immune system and possible therapeutic options in the treatment of PC.

Simultaneous microRNA-612 restoration and 5-FU treatment inhibit the growth and migration of human PANC-1 pancreatic cancer cells.

Despite the recent advances in the treatment of other cancers, the 5-year survival rate of pancreatic cancer remains under 9 %. Chemotherapy and surgical resection are the most common therapy methods. The regulatory role of microRNAs in different types of cancer has given them therapeutic importance. miR-612 has been downregulated in colorectal, bladder, liver, and some other types of cancer and could be considered a tumor-suppressor miRNA. 5-FU is one of the most common chemotherapeutic agents used in pancreatic cancer treatment, which is used in multiple drug regimens and combinatorial therapy methods. The aim of this study is the evaluation of miR-612 restoration in the PANC-1 cell line and using the tumor-suppressive effect of it in combination with 5-FU on cell growth and migration. MiR-612 mimic was transfected to PANC-1 cells through electroporation. Following the transfection, expression levels of miR-612 and BAX, BCL-2, Caspase-3, MMP9, and PD-L1 genes were measured by qRT-PCR. MTT assay was used to determine the cytotoxicity of miR-612 and 5-FU on PANC-1 cell viability. To confirm MTT results and to evaluate the quantitative effect of apoptosis induction flow cytometry test was used and in order to confirm apoptosis test results and cell cycle arrest evaluation DAPI staining and cell, cycle tests were conducted, respectively. Finally, to assess the inhibitory effect of miR-612 in combination with 5-FU on migration and growth wound healing and colony formation assays were used, respectively. Results demonstrated that miR-612 alongside 5-FU has an important role in the inhibition of migration and growth and also apoptosis induction in PANC-1 cells and could be considered as a supporting agent of chemotherapy and a novel therapeutic modality in pancreatic cancer treatment.

The roles of signaling pathways in SARS-CoV-2 infection; lessons learned from SARS-CoV and MERS-CoV.

The number of descriptions of emerging viruses has grown at an unprecedented rate since the beginning of the 21st century. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), is the third highly pathogenic coronavirus that has introduced itself into the human population in the current era, after SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Molecular and cellular studies of the pathogenesis of this novel coronavirus are still in the early stages of research; however, based on similarities of SARS-CoV-2 to other coronaviruses, it can be hypothesized that the NF-κB, cytokine regulation, ERK, and TNF-α signaling pathways are the likely causes of inflammation at the onset of COVID-19. Several drugs have been prescribed and used to alleviate the adverse effects of these inflammatory cellular signaling pathways, and these might be beneficial for developing novel therapeutic modalities against COVID-19. In this review, we briefly summarize alterations of cellular signaling pathways that are associated with coronavirus infection, particularly SARS-CoV and MERS-CoV, and tabulate the therapeutic agents that are currently approved for treating other human diseases.