The Role of the MCTS1 and DENR Proteins in Regulating the Mechanisms Associated with Malignant Cell Transformation

The mutations associated with malignant cell transformation are believed to disrupt the expression of a significant number of normal, non-mutant genes. The proteins encoded by these genes are involved in the regulation of many signaling pathways that are responsible for differentiation and proliferation, as well as sensitivity to apoptotic signals, growth factors, and cytokines. Abnormalities in the balance of signaling pathways can lead to the transformation of a normal cell, which results in tumor formation. Detection of the target genes and the proteins they encode and that are involved in the malignant transformation is one of the major evolutions in anti-cancer biomedicine. Currently, there is an accumulation of data that shed light on the role of the MCTS1 and DENR proteins in oncogenesis.

Mutations in MED12 lead to mental retardation, including Opitz–Kaveggia syndrome, Ohdo syndrome, Lujan–Fryns syndrome, and psychosis. It's a target for gene therapy

Mutations in MED12 lead to mental retardation, including Opitz–Kaveggia syndrome, Ohdo syndrome, Lujan–Fryns syndrome, and psychosis. Malignant cell transformation was linked to a transcriptional machine failure and, as such, MED12 function dysregulation was engaged across many cancers. Its involvement in hormone-dependent cancers (uterine leiomyoma, breast fibroepithelial tumors, prostate cancer, and breast cancer) represents a unique target for such malignancies. Knowledge of downstream targets of MED12 alterations also includes specific targets that might be exploited in MED 12-mutated cancers. For example, MED 12 loss entails resistance to lung cancer tyrosine kinase inhibitors, pushing emphasis to alternative therapies. The entire genome sequencing area is growing quite rapidly, so we anticipate identifying MED12 mutations more regularly in people with intellectual disability. It is also worth noting that gene location on chromosome X mainly affects males, causing such gender bias illnesses. The study was published in the journal of Clinical and molecular Epidemiology, Biomarkers' Journal. The study concluded that MED12 is a crucial component of transcription regulatory machinery and any alterations in its structure or function are deleterious to cell growth, division, and differentiation processes. MED12 is, thus, a major transcription regulator affecting various behavioral disorders and malignancies. This research suffices to identify MED12 as a therapeutic target and biomarker for several diseases.

AKR1B10 negatively regulates autophagy through reducing GAPDH upon glucose starvation in colon cancer

ABSTRACT Autophagy is considered to be an important switch for facilitating normal to malignant cell transformation during colorectal cancer development. Consistent with other reports, we found that the membrane receptor Neuropilin1 (NRP1) is greatly upregulated in colon cancer cells that underwent autophagy upon glucose deprivation. However, the mechanism underlying NRP1 regulation of autophagy is unknown. We found that knockdown of NRP1 inhibits autophagy and largely upregulates the expression of aldo-keto reductase family 1 B10 (AKR1B10). Moreover, we demonstrated that AKR1B10 interacts with and inhibits the nuclear importation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and then subsequently represses autophagy. Interestingly, we also found that an NADPH-dependent reduction reaction could be induced when AKR1B10 interacts with GAPDH, and the reductase activity of AKR1B10 is important for its repression of autophagy. Together, our findings unravel a novel mechanism of NRP1 in regulating autophagy through AKR1B10.

MicroRNA profiling in BEAS-2B cells exposed to alpha radiation reveals potential biomarkers for malignant cellular transformation

The carcinogenicity of radon has been convincingly documented through epidemiological studies of underground miners. The risk of lung cancer from radon exposure is due to the continuous radioactive decay of this gas and subsequent emission of high-energy alpha decay particles. And the bronchial epithelial cells are the main targets of radon exposure. However, there is a lack of early warning indicators of lung cancer caused by radon in the physical examination of populations involved in occupations with higher exposure to radon. To assess the potential of a molecular-based marker approach for the early detection of human lung cancer induced by radon, human bronchial epithelial cell injury models induced by alpha-particle irradiation were constructed. The results of transwell migration assay, transwell invasion assay, and the expression of the epithelial–mesenchymal transition-related proteins showed that malignant cell transformation could be triggered by alpha irradiation. Potential microRNAs (miRNAs) (hsa-miR-3907, hsa-miR-6732-3p, hsa-miR-4788, hsa-miR-5001-5p, and hsa-miR-4257) were screened using miRNA chips in cell models. The pathway analyses of miRNAs selected using DIANA-miRPath v3.0 showed that miRNAs involved in malignant cell transformation were associated with cell adhesion molecules, extracellular matrix receptor interaction, and proteoglycans in cancer, among others, which are closely related to the occurrence and development of carcinogenesis. Reverse Transcription Quantitative Real-Time PCR (RT-qPCR) assay showed that five screened miRNAs were up-regulated in five lung cancer tissue samples. In conclusion, the results indicated that hsa-miR-3907, hsa-miR-6732-3p, hsa-miR-4788, hsa-miR-5001-5p, and hsa-miR-4257 may be potential early markers of the malignant transformation of bronchial epithelial cells induced by alpha-particle irradiation.

Synthesis and in vitro characterization of the genotoxic, mutagenic and cell-transforming potential of nitrosylated heme

Data from epidemiological studies suggest that consumption of red and processed meat is a factor contributing to colorectal carcinogenesis. Red meat contains high amounts of heme, which in turn can be converted to its nitrosylated form, NO-heme, when adding nitrite-containing curing salt to meat. NO-heme might contribute to colorectal cancer formation by causing gene mutations and could thereby be responsible for the association of (processed) red meat consumption with intestinal cancer. Up to now, neither in vitro nor in vivo studies characterizing the mutagenic and cell transforming potential of NO-heme have been published due to the fact that the pure compound is not readily available. Therefore, in the present study, an already existing synthesis protocol was modified to yield, for the first time, purified NO-heme. Thereafter, newly synthesized NO-heme was chemically characterized and used in various in vitro approaches at dietary concentrations to determine whether it can lead to DNA damage and malignant cell transformation. While NO-heme led to a significant dose-dependent increase in the number of DNA strand breaks in the comet assay and was mutagenic in the HPRT assay, this compound tested negative in the Ames test and failed to induce malignant cell transformation in the BALB/c 3T3 cell transformation assay. Interestingly, the non-nitrosylated heme control showed similar effects, but was additionally able to induce malignant transformation in BALB/c 3T3 murine fibroblasts. Taken together, these results suggest that it is the heme molecule rather than the NO moiety which is involved in driving red meat-associated carcinogenesis.

Enhanced C/EBPs binding to C>T mismatches facilitates fixation of CpG mutations

Knowledge of mechanisms responsible for mutagenesis of adult stem cells is crucial to track genomic alterations that may affect cell renovation and provoke malignant cell transformation. Mutations in regulatory regions are widely studied nowadays, though mostly in cancer. In this study, we decomposed the mutation signature of adult stem cells, mapped the corresponding mutations into transcription factor binding regions, and assessed mutation frequency in sequence motif occurrences. We found binding sites of C/EBP transcription factors strongly enriched with [C>T]G mutations within the core CG dinucleotide related to deamination of the methylated cytosine. This effect was also exhibited in related cancer samples. Structural modeling predicted enhanced CEBPB binding to the consensus sequence with the [C>T]G mismatch, which was then confirmed in the direct experiment. We propose that it is the enhanced binding of C/EBPs that shields C>T transitions from DNA repair and leads to selective accumulation of the [C>T]G mutations within binding sites.

An Overview of the Epigenetic Modifications of Gene Expression in Tumorigenesis

The five leading causes of cancer-related deaths are lung (1,760,000 deaths), colorectal (862,000 deaths), stomach (783,000 deaths), liver (782,000 deaths), and breast (627,000 deaths) cancers. Epigenetic changes can alter chromatin compaction, leading to the regulation of gene expression without changing the primary DNA sequence. Epigenetic mechanisms are normally involved in cellular processes such as genomic stability, chromosome X inactivation, and embryonic development and differentiation. Similar to other types of chromatin modifications, DNA methylation has been verified to affect the expression of various genes. Any impairment in these mechanisms alters the regulation of gene expression and can contribute to malignant cell transformation. Over the past few years, extensive innovations within the field of epigenetics have encouraged its application as a major strategy for the treatment of important diseases such as cancer.