Revolutionizing colorectal cancer treatment: unleashing the potential of miRNAs in targeting cancer stem cells.

Colorectal cancer (CRC) is a significant contributor to cancer mortality worldwide, and the presence of cancer stem cells (CSC) represents a major challenge for achieving effective treatment. miRNAs have emerged as critical regulators of gene expression, and recent studies have highlighted their role in regulating stemness and therapeutic resistance in CRC stem cells. This review highlights the mechanisms of CSC development, therapy resistance and the potential of miRNAs as therapeutic targets for CRC. It emphasizes the promise of miRNAs as a novel approach to CRC treatment and calls for further research to explore effective miRNA-based therapies and strategies for delivering miRNAs to CSCs in vivo.

Analysis of self-renewing and differentiation-related microRNAs and transcription factors in multilineage mouse hematopoietic stem/progenitor cells induced by 1,4-benzoquinone.

Background: HSPCs are targets for benzene-induced hematotoxicity and leukemogenesis. However, benzene toxicity targeting microRNAs (miRNAs) and transcription factors (TF) that are involve in regulating self-renewing and differentiation of HSPCs comprising of different hematopoietic lineages remains poorly understood. In this study, the effect of a benzene metabolite, 1,4-benzoquinone (1,4-BQ) exposure, in HSPCs focusing on the self-renewing (miRNAs: miR-196b and miR-29a; TF: HoxB4, Bmi-1) and differentiation (miRNAs: miR-181a, TF: GATA3) pathways were investigated. Methods: Freshly isolated mouse BM cells were initially exposed to 1,4-BQ at 1.25 to 5 µM for 24 h, followed by miRNAs and TF studies in BM cells. Then, the miRNAs expression was further evaluated in HSPCs of different lineages comprised of myeloid, erythroid and pre-B lymphoid progenitors following 7-14 days of colony forming unit (CFU) assay. Results: Exposure to 1,4-BQ in BM cells significantly (p < 0.05) reduced the miR-196b (2.5 and 5 µM), miR-181a (1.25, 2.5 and 5 µM) and miR-29a (1.25 µM) along with upregulation of miR-29a at 2.5 µM. Meanwhile, 1,4-BQ exposure in HSPCs significantly increased the miR-196b expression level (p < 0.05) only in myeloid and pre-B lymphoid progenitors at 2.5 and 5 µM. Significant (p < 0.05) reduction in expression of miR-181a in myeloid (1.25 µM), erythroid (5 µM) progenitors along with miR-29a in myeloid (1.25 µM) and pre-B lymphoid (5 µM) progenitors were noted following exposure to 1,4-BQ. Meanwhile, increased expression of miR-181a was observed in pre-B lymphoid progenitor upon exposure to 1,4-BQ, but only at 5 µM. As for TF studies, expression of HoxB4 protein was significantly increased (p < 0.05) at all 1,4-BQ concentrations as compared to Bmi-1 and GATA3, which were significantly (p < 0.05) elevated starting at 2.5 µM of 1,4-BQ. Conclusion: 1,4-BQ induces aberration of miRNAs and transcription factors protein expression that are involved in regulating self-renewing and differentiation pathways of HSPCs. Moreover, epigenetic toxicity as evidenced from the miRNAs expression was found to be mediated by a lineage-driven mechanism. The role of cell lineage in governing the toxicity of 1,4-BQ in HSPCs lineages deserves further investigation.

Ferroptosis as a potential target for cancer therapy.

Ferroptosis is a recently discovered essential type of cell death that is mainly characterized by iron overload and lipid peroxidation. Emerging evidence suggests that ferroptosis is a double-edged sword in human cancer. However, the precise underlying molecular mechanisms and their differential roles in tumorigenesis are unclear. Therefore, in this review, we summarize and briefly present the key pathways of ferroptosis, paying special attention to the regulation of ferroptosis as well as its dual role as an oncogenic and as a tumor suppressor event in various human cancers. Moreover, multiple pharmacological ferroptosis activators are summarized, and the prospect of targeting ferroptosis in cancer therapy is further elucidated.

A review on mechanobiology of cell adhesion networks in different stages of sporadic colorectal cancer to explain its tumorigenesis.

Sporadic colorectal cancer (CRC) is strongly linked to extraneous factors, like poor diet and lifestyle, but not to inherent factors like familial genetics. The changes at the epigenomics and signalling pathways are known across the sporadic CRC stages. The catch is that temporal information of the onset, the feedback loop, and the crosstalk of signalling and noise are still unclear. This makes it challenging to diagnose and treat colon cancer effectively with no relapse. Various microbial cells and native cells of the colon, contribute to sporadic CRC development. These cells secrete autocrine and paracrine for their bioenergetics and communications with other cell types. Imbalances of the biochemicals affect the epithelial lining of colon. One side of this epithelial lining is interfacing the dense colon tissue, while the other side is exposed to microbiota and excrement from the lumen. Hence, the epithelial lining is prone to tumorigenesis due to the influence of both biochemical and mechanical cues from its complex surrounding. The role of physical transformations in tumorigenesis have been limitedly discussed. In this context, cellular and tissue structures, and force transductions are heavily regulated by cell adhesion networks. These networks include cell anchoring mechanism to the surrounding, cell structural integrity mechanism, and cell effector molecules. This review will focus on the progression of the sporadic CRC stages that are governed by the underlaying cell adhesion networks within the epithelial cells. Additionally, current and potential technologies and therapeutics that target cell adhesion networks for treatments of sporadic CRC will be incorporated.

Bone Marrow Oxidative Stress and Acquired Lineage-Specific Genotoxicity in Hematopoietic Stem/Progenitor Cells Exposed to 1,4-Benzoquinone.

Hematopoietic stem/progenitor cells (HSPCs) are susceptible to benzene-induced genotoxicity. However, little is known about the mechanism of DNA damage response affecting lineage-committed progenitors for myeloid, erythroid, and lymphoid. Here, we investigated the genotoxicity of a benzene metabolite, 1,4-benzoquinone (1,4-BQ), in HSPCs using oxidative stress and lineage-directed approaches. Mouse bone marrow cells (BMCs) were exposed to 1,4-BQ (1.25-12 µM) for 24 h, followed by oxidative stress and genotoxicity assessments. Then, the genotoxicity of 1,4-BQ in lineage-committed progenitors was evaluated using colony forming cell assay following 7-14 days of culture. 1,4-BQ exposure causes significant decreases (p < 0.05) in glutathione level and superoxide dismutase activity, along with significant increases (p < 0.05) in levels of malondialdehyde and protein carbonyls. 1,4-BQ exposure induces DNA damage in BMCs by significantly (p < 0.05) increased percentages of DNA in tail at 7 and 12 µM and tail moment at 12 µM. We found crucial differences in genotoxic susceptibility based on percentages of DNA in tail between lineage-committed progenitors. Myeloid and pre-B lymphoid progenitors appeared to acquire significant DNA damage as compared with the control starting from a low concentration of 1,4-BQ exposure (2.5 µM). In contrast, the erythroid progenitor showed significant damage as compared with the control starting at 5 µM 1,4-BQ. Meanwhile, a significant (p < 0.05) increase in tail moment was only notable at 7 µM and 12 µM 1,4-BQ exposure for all progenitors. Benzene could mediate hematological disorders by promoting bone marrow oxidative stress and lineage-specific genotoxicity targeting HSPCs.

DNA Methylation Is Involved in the Expression of miR-142-3p in Fibroblasts and Induced Pluripotent Stem Cells.

MicroRNAs are differentially expressed in cells and regulate multiple biological processes. We have been analyzing comprehensive expression patterns of microRNA in human and mouse embryonic stem and induced pluripotent stem cells. We determined microRNAs specifically expressed in these pluripotent stem cells, and miR-142-3p is one of such microRNAs. miR-142-3p is expressed at higher levels in induced pluripotent stem cells relative to fibroblasts in mice. Level of expression of miR142-3p decreased during embryoid body formation from induced pluripotent stem cells. Loss-of-function analyses of miR-142-3p suggested that miR-142-3p plays roles in the proliferation and differentiation of induced pluripotent stem cells. CpG motifs were found in the 5' genomic region of the miR-142-3p; they were highly methylated in fibroblasts, but not in undifferentiated induced pluripotent stem cells. Treating fibroblasts with 5-aza-2'-deoxycytidine increased the expression of miR-142-3p significantly and reduced methylation at the CpG sites, suggesting that the expression of miR-142-3p is suppressed by DNA methylation in fibroblasts. Luciferase analysis using various lengths of the 5' genomic region of miR142-3p indicated that CpGs in the proximal enhancer region may play roles in suppressing the expression of miR-142-3p in fibroblasts.