Steroid receptor RNA activator gene footprint in the progression and drug resistance of colorectal cancer through oxidative phosphorylation pathway.

BACKGROUND: The steroid receptor RNA activator 1 (SRA1) gene is involved in the progression of various cancers via different molecular mechanisms mediated by long non-coding RNA SRA (lncRNA SRA). This study aimed to evaluate the lncRNA SRA effect on the tumor progression of colorectal cancer (CRC). METHODS: SRA1 expression was assessed in the cancer genome atlas datasets, CRC cell lines, and tumor specimens. Meta-analysis and gene co-expression network analysis were performed to identify pathways related to SRA1. RNA interference and cell treatment were utilized to examine the role of SRA1 expression in HT-29 and Caco-2 cell lines. Also, the effect of SRA1 expression was investigated on drug resistance, clinical parameters, and mutations in CRC samples. RESULTS: The SRA1 transcripts, especially lncRNA SRA, were dysregulated in CRC tissue samples compared with normal tissue samples. Furthermore, SRA1 depletion decreased colony formation and proliferation while induced apoptosis in HT-29 and Caco-2 cells. In silico analyses indicated that SRA1 level was correlated with expression levels of oxidative phosphorylation (OXPHOS) genes. LncRNA SRA expression increased in response to the increased oxidative capacity, and when lncRNA SRA was knocked down, the expression level of OXPHOS pathway genes, including NDUFB5 and ATP5F1B, was changed. Also, KRAS-mutant samples had the highest SRA1 expression level. CONCLUSIONS: LncRNA SRA could function as an oncogene through the OXPHOS pathway in CRC, and serve as a potential biomarker for identifying CRC subtype with KRAS mutations. The findings suggest that lncRNA SRA might be a therapeutic target to inhibit cell proliferation in CRC.

A combination of herbal compound (SPTC) along with exercise or metformin more efficiently alleviated diabetic complications through down-regulation of stress oxidative pathway upon activating Nrf2-Keap1 axis in AGE rich diet-induced type 2 diabetic mice.

BACKGROUND: SPTC is a mix of four herbal components (Salvia officinalis, Panax ginseng, Trigonella foenum-graeceum, and Cinnamomum zeylanicum) which might be prevented the development of AGE rich diet-induced diabetic complication and liver injury through activated the nuclear factor erythroid-2-related-factor-2 (Nrf2) pathway. Nrf2, as a master regulator of antioxidant response elements by activating cytoprotective genes expression, is decreased oxidative stress that associated with hyperglycemia and increases insulin sensitivity. the aim of this study was to assess whether the combination therapy of SPTC along with exercise or metformin moderate oxidative stress related liver injurie with more favorable effects in the treatment of AGE rich diet-induced type 2 diabetic mice. METHODS: We induced diabetes in C57BL/6 mice by AGE using a diet supplementation and limitation of physical activity. After 16 weeks of intervention, AGE fed mice were compared to control mice. Diabetic mice were assigned into seven experimental groups (each group; n = 5): diabetic mice, diabetic mice treated with SPTC (130 mg/kg), diabetic mice treated with Salvia Officinalis (65 mg/kg), diabetic mice treated with metformin (300 mg/kg), diabetic mice with endurance exercise training, diabetic mice treated with SPTC + metformin (130/300 mg/kg), diabetic mice treated with SPTC + exercise training. RESULTS: SPTC + exercise and SPTC + metformin reduced diabetic complications like gain weight, water and calorie intake, blood glucose, insulin, and GLUT4 content more efficiently than each treatment. These combinations improved oxidative stress hemostasis by activating the Nrf2 signaling pathway and attenuating keap1 protein more significantly. CONCLUSION: Eventually, combined treatment of SPTC with exercise or metformin as a novel approach had more beneficial effects to prevent the development of diabetes and oxidative stress associated with hyperglycemia.

Mechanistic Pathways of Malignancy in Breast Cancer Stem Cells.

Breast cancer stem cells (BCSCs) are the minor population of breast cancer (BC) cells that exhibit several phenotypes such as migration, invasion, self-renewal, and chemotherapy as well as radiotherapy resistance. Recently, BCSCs have been more considerable due to their capacity for recurrence of tumors after treatment. Recognition of signaling pathways and molecular mechanisms involved in stemness phenotypes of BCSCs could be effective for discovering novel treatment strategies to target BCSCs. This review introduces BCSC markers, their roles in stemness phenotypes, and the dysregulated signaling pathways involved in BCSCs such as mitogen-activated protein (MAP) kinase, PI3K/Akt/nuclear factor kappa B (NFκB), TGF-ß, hedgehog (Hh), Notch, Wnt/ß-catenin, and Hippo pathway. In addition, this review presents recently discovered molecular mechanisms implicated in chemotherapy and radiotherapy resistance, migration, metastasis, and angiogenesis of BCSCs. Finally, we reviewed the role of microRNAs (miRNAs) in BCSCs as well as several other therapeutic strategies such as herbal medicine, biological agents, anti-inflammatory drugs, monoclonal antibodies, nanoparticles, and microRNAs, which have been more considerable in the last decades.

Role of non-coding RNAs as novel biomarkers for detection of colorectal cancer progression through interaction with the cell signaling pathways.

Colorectal cancer (CRC) is one of the most common types of cancer which affects the colon and the rectum. Approximately one third of annual CRC mortality occurs due to the late detection of this type of cancer. Therefore, there is an urgent need for more powerful diagnostic and prognostic tools for identification and treatment of colorectal tumorigenesis. Non-coding RNAs (ncRNAs) have been implicated in the pathology of CRC and also linked to metastasis, proliferation, differentiation, migration, angiogenesis and apoptosis in numerous cancers. Recently, attention has turned towards ncRNAs as specific targets for diagnosis, prognosis and treatment of various types of cancers, including CRC. In this review, we have tried to outline the roles of ncRNAs, and their involvement in signaling pathways responsible for the progression of CRC.

Signaling pathways involved in colorectal cancer progression.

Colorectal cancer (CRC) is the fourth leading cause of the worldwide cancer mortality. Different molecular mechanisms have been attributed to the development and progress of CRC. In this review, we will focus on the mitogen-activated protein kinase (MAPK) cascades downstream of the epidermal growth factor receptor (EGFR), Notch, PI3K/AKT pathway, transforming growth factor-ß (TGF-ß), and Wnt signaling pathways. Various mutations in the components of these signaling pathways have been linked to the development of CRC. Accordingly, numerous efforts have been carried out to target the signaling pathways to develop novel therapeutic approaches. Herein, we review the signaling pathways involved in the incidence and progression of CRC, and the strategies for the therapy targeting components of signaling pathways in CRC.

Characterization of the stemness potency of mammospheres isolated from the breast cancer cell lines.

Stemness phenotype mammospheres established from cell lines and tissues taken from autopsy can be used to test and to identify the most sensitive drugs for chemotherapy. Therefore, the aim of the present study was isolation and characterization of cancer stem cells derived from MCF7, MDA-MB231, and SKBR3 breast cancer cell lines to demonstrate the stemness phenotypes of mammospheres generated for further their applications in therapeutic approaches. In this study, two luminal subtypes of cell lines, MCF7 and SKBR3 and a basal subtype cell line, MDA-MB-231, were chosen. Mammosphere culturing was implemented for breast cancer stem cells isolation and mammosphere formation efficiency. At the next step, CD44+/CD24- cell ratio, Oct4 and Nanog mRNA levels, proliferation rate, migration rate of mammospheres, and drug resistance (in third passage) were evaluated. In addition, tumorigenicity of mammospheres in the chick embryo model was evaluated and compared through the chick chorioallantoic membrane assay. Among mammospheres formed in all three cell lines, MCF7 had the highest mammosphere formation efficiency. CD24 marker (a differentiation marker for the breast cancer cells) was significantly reduced in the mammospheres generated from MCF7 and SKBR3, during three passages. Also, Oct4 and Nanog transcript levels were significantly higher in all three types of mammospheres, as compared with their cell lines. Proliferation, migration rate, and drug resistance of mammospheres generated from all three cell lines were found to be significantly higher. Tumorigenicity of MCF7 mammospheres was confirmed through tumor size measurement. Also, tumorigenicity of MCF7 and SKBR3 mammospheres was confirmed through more migration from ectoderm to mesoderm and endoderm. We succeeded to establish the technology that can be extended to tissue in the future. We have demonstrated a number of mammospheres can be generated from cell lines. Also, cells with different molecular features showed different stemness phenotypes.

Diverse roles of fatty acid binding proteins (FABPs) in development and pathogenesis of cancers.

One of the most importantly involved pathways in cancer development is fatty-acid signaling pathway. Synthesized lipids as energetic sources are consumed by cancer cells for proliferation, growth, survival, invasion and angiogenesis. Fatty acids as signaling compounds regulate metabolic and transcriptional networks, survival pathways and inflammatory responses. Aggregation of fatty acids with fatty acid binding proteins (FABPs) facilitates their transportation to different cell organelles. FABPs, a group of lipid binding proteins modulate fatty acid metabolism, cell growth and proliferation and cancer development. They may be used as tumor marker in some cancers. FABPs are expressed in most malignancies such as prostate, breast, liver, bladder and lung cancer which are associated with the incidence, proliferation, metastasis, invasion of tumors. This review introduces several isoforms of FABPs (FABP1-12) and summarizes their function and their possible roles in cancer development through some proposed mechanisms.

The influence of peroxisome proliferator-activated receptor γ (PPARγ) ligands on cancer cell tumorigenicity.

Peroxisome proliferator-activated receptor γ (PPARγ) belongs to the nuclear receptor superfamily of PPARs (PPARα, PPARß/δ, PPARγ). Numerous studies have concentrated on the key role of PPARs in inflammation and a variety of cancers which include prostate, breast, glioblastoma, neuroblastoma, pancreatic, hepatic, leukemia, and bladder and thyroid tumors. This review, specifically deals with anti-tumor and tumorigenicity effects of PPARγ and its natural and synthetic agonists including Troglitazone, Cladosporol A, B, 15-Deoxi-Δ12-14-Prostaglondin J2 (15-d-PGJ2), Ciglitazon, docosahexaenoic acid, eicosapentaenoic acid Alpha-eleostreac acid, Amorfrutin C, Sphingosine 1-phosphate, Evodiamine, Excavatolide B vs respected antagonists as GW9662, bisphenol-A-diglycidyl-ether. Considering the contradictory role of PPARγ on tumorigenicity, a number of studies demonstrate mechanisms involved in tumorigenicity effects of PPARγ agonists while several studies suggest key roles of PPARγ agonists in anti-proliferation, metastasis, angiogenesis, apoptosis and immunomodulatory through activation of signaling pathways in different cancer cells as well as in cancer stem cells. The aim of this review is summarizing of tumorigenicity and anti-tumorigenicity activities of PPARγ agonists and antagonists as well as therapeutic activities of these reagents as a coadjutant drug in the treatment of different cancers.