Current Gene Therapy - Volume 23, Issue 5, 2023

The second most pervasive cancer affecting the survival of women across the world is breast cancer. One of the biggest challenges in breast cancer treatment is the chemoresistance of cancer cells to various medications after some time. Therefore, highly specific blood-based biomarkers are required for early breast cancer diagnosis to overcome chemoresistance and improve patient survival. These days, exosomal miRNAs have attracted much attention as early diagnostic blood-based biomarkers because of their high stability, secretion from malignant tumor cells, and excellent specificity for different breast cancer subtypes. In addition, exosomal miRNAs regulate cell proliferation, invasion, metastasis, and apoptosis by binding to the 3′UTR of their target genes and limiting their production. This review focuses on the functions of exosomal miRNAs in tumorigenesis via targeting multiple signaling pathways as well as chemosensitivity and resistance mechanisms. In addition, the growing pieces of evidence discussed in this review suggest that circulating exosomal miRNAs could be utilized as potential next-generation therapeutic target vehicles in the treatment of breast cancer.

MicroRNAs (miRNAs - ~22 nucleotides) are a type of non-coding RNAs that are involved in post-transcriptional gene silencing. They are known to regulate gene expression in diverse biological processes, such as apoptosis, development, and differentiation. Several studies have demonstrated that cancer initiation and progression are highly regulated by miRNA expression. The nutrients present in the diet may regulate the different stages of carcinogenesis. Interestingly, plant-based foods, like fruits and vegetables, have been shown to play a significant role in cancer prevention. Phytochemicals are bioactive compounds derived from plant sources, and they have been shown to have antiinflammatory, antioxidant, and anticancer properties. Recent findings suggest that dietary phytochemicals, such as genistein, resveratrol, and curcumin, exert significant anticancer effects by regulating various miRNAs. In this review, we focus on the role of dietary phytochemicals in cancer prevention and treatment through the modulation of miRNA expression.

Background:: Radiotherapy is a standard adjuvant therapy in patients with progressive rectal cancer, but many patients are resistant to radiotherapy, leading to poor prognosis. Our study identified microRNA-652 (miR-652)value on radiotherapy response and outcome in rectal cancer patients. Methods: miR-652expression was determined by qPCR in primary rectal cancer from 48 patients with and 53 patients without radiotherapy. The association of miR-652with biological factors and the prognosis was examined. The biological function of miR-652was identified through TCGA and GEPIA database searches. Two human colon cancer cell lines (HCT116 p53^+/+ and p53^-/-) were used for in vitro study. The molecular interactions of miR-652and tumor suppressor genes were studied through a computational approach. Results: In RT patients, miR-652expression was significantly decreased in cancers when compared to non-radiotherapy cases (P= 0.002). High miR-652expression in non-RT patients was with increased apoptosis marker (P= 0.036), ATM (P= 0.010), and DNp73 expression (P= 0.009). High miR-652 expression was related to worse disease-free survival of non-radiotherapy patients, independent of gender, age, tumor stage, and differentiation (P= 0.028; HR = 7.398, 95% CI 0.217-3.786). The biological functional analysis further identified the prognostic value and potential relationship of miR-652 with apoptosis in rectal cancer. miR-652expression in cancers was negatively related to WRAP53 expression (P= 0.022). After miR-652inhibition, the estimation of reactive oxygen species, caspase activity, and apoptosis in HCT116 p53^+/+ cells was significantly increased compared with HCT116 p53^-/- cells after radiation. The results of the molecular docking analysis show that the miR652-CTNNBL1 and miR652-TP53 were highly stable. Conclusion: Our findings suggest the potential value of miR-652expression as a marker for the prediction of radiation response and clinical outcome in rectal cancer patients.

Background: N⁶-methyladenosine (m⁶A) is the most frequent internal modification in eukaryotic RNA. Long noncoding RNAs (lncRNAs) are a new type of noncoding regulatory molecule with multiple cellular functions. Both are closely related to the occurrence and development of liver fibrosis (LF). However, the role of m⁶A-methylated lncRNAs in the progression of LF remains largely unknown. Methods: In this study, HE and Masson staining were used to observe pathological changes in the liver, m⁶A-modified RNA immunoprecipitation sequencing (m⁶A-seq) was performed to systematically evaluate the m⁶A modification level of lncRNAs in LF mice, meRIP-qPCR and RT-qPCR were used to detect the m⁶A methylation level and RNA expression level of the target lncRNAs. Results: A total of 415 m⁶A peaks were detected in 313 lncRNAs in liver fibrosis tissues. There were 98 significantly different m⁶A peaks in LF, which were located on 84 lncRNAs, of which 45.2% of the lncRNA length was between 200-400 bp. At the same time, the first three chromosomes of these methylated lncRNAs were chromosomes 7, 5 and 1. RNA sequencing identified 154 differentially expressed lncRNAs in LF. The joint analysis of m⁶A-seq and RNA-seq found that there were three lncRNAs with significant changes in m⁶A methylation and RNA expression levels: lncRNA H19, lncRNA Gm16023 and lncRNA Gm17586. Subsequently, the verification results showed that the m⁶A methylation levels of lncRNA H19 and lncRNA Gm17586 were significantly increased, while that of lncRNA Gm16023 was significantly decreased, and the RNA expression of three lncRNAs was significantly decreased. Through the establishment of a lncRNA-miRNA-mRNA regulatory network, the possible regulatory relationships of lncRNA H19, lncRNA Gm16023 and lncRNA Gm17586 in LF were revealed. Conclusion: This study revealed the unique m⁶A methylation pattern of lncRNAs in LF mice, suggesting that the m⁶A methylation modification of lncRNAs is related to the occurrence and development of LF.

Introduction: Gastric cancer is a well-known malignant tumor that causes millions of deaths worldwide every year. Due to the lack of a specific biomarker for gastric cancer, most patients are diagnosed at an advanced stage of the disease which results in a poor prognosis and a higher death rate. Therefore, novel biomarkers are urgently needed for early diagnosis and to improve the survival rate. Methods: In this study, we conducted RNA sequencing of tumor samples from 21 patients with gastric cancer. A total of 3192 differentially expressed genes (1589 up-regulated and 1603 down-regulated) were identified. Subsequently, we applied a text-mining algorithm for further analysis of these data and selected 30 representative genes to investigate as candidates for novel biomarkers in gastric cancer. Results: Among these genes, we confirmed transient receptor potential melastatin 8 channels (TRPM8) as a novel biomarker based on Western blot and immunochemistry validation performed on 134 samples. Compared to normal gastric tissue, the tumor tissues exhibited a significantly higher expression level of TRPM8. Conclusion: This study provides insights into the underlying role of TRPM8 in cell proliferation. In addition, TRPM8 may be used as a potential therapeutic target for patients with gastric cancer.

Introduction: Hydrocephalus is a common pediatric disorder of cerebral spinal fluid physiology resulting in abnormal expansion of the cerebral ventricles. However, the underlying molecular mechanisms remain unknown. Methods: We performed proteomic analyses of cerebrospinal fluid (CSF) from 7 congenital hydrocephalus and 5 arachnoid cyst patients who underwent surgical treatment. Differentially expressed proteins (DEPs) were identified by label-free Mass Spectrometry followed by differential expression analysis. The GO and GSEA enrichment analysis was performed to explore the cancer hallmark pathways and immune-related pathways affected by DEPs. Then, network analysis was applied to reveal the location of DEPs in the human protein-protein interactions (PPIs) network. Potential drugs for hydrocephalus were identified based on drug-target interaction. Results: We identified 148 up-regulated proteins and 82 down-regulated proteins, which are potential biomarkers for clinical diagnosis of hydrocephalus and arachnoid cyst. Functional enrichment analysis revealed that the DEPs were significantly enriched in the cancer hallmark pathways and immunerelated pathways. In addition, network analysis uncovered that DEPs were more likely to be located in the central regions of the human PPIs network, suggesting DEPs may be proteins that play important roles in human PPIs. Finally, we calculated the overlap of drug targets and the DEPs based on drugtarget interaction to identify the potential therapeutic drugs of hydrocephalus. Conclusion: The comprehensive proteomic analyses provided valuable resources for investigating the molecular pathways in hydrocephalus, and uncovered potential biomarkers for clinical diagnosis and therapy.

Background: DNA hypermethylation plays a critical role in the occurrence and progression of acute myeloid leukemia (AML). The mitochondrial serine transporter, SFXN3, is vital for onecarbon metabolism and DNA methylation. However, the impact of SFXN3 on the occurrence and progression of AML has not been reported yet. Objective: In this study, we hypothesized that SFXN3 indicates a poor prognosis and suggested tailored treatment for AML patients. Methods: We used GEPIA and TCGA repository data to analyze the expression of SFXN3 and its correlation with survival in AML patients. RT-qPCR was used to detect the SFXN3 level in our enrolled AML patients and volunteers. Additionally, Whole Genome Bisulfite Sequencing (WGBS) was used to detect the genomic methylation level in individuals. Results: Through the TCGA and GEPIA databases, we found that SFXN3 was enriched in AML patients, predicting shorter survival. Furthermore, we confirmed that SFXN3 was primarily overexpressed in AML patients, especially non-M3 patients, and that high SFXN3 in non-M3 AML patients was found to be associated with poor outcomes and frequent blast cells. Interestingly, non-M3 AML patients with high SFXN3 levels who received hypomethylating therapy showed a higher CR ratio. Finally, we found that SFXN3 could promote DNA methylation at transcription start sites (TSS) in non-M3 AML patients. These sites were found to be clustered in multiple vital cell functions and frequently accompanied by mutations in DNMT3A and NPM1. Conclusion: In conclusion, SXFN3 plays an important role in the progression and hypermethylation in non-M3 AML patients and could be a potential biomarker for indicating a high CR rate for hypomethylating therapy.