miR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2.

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by cytopenia and extramedullary hematopoiesis, resulting in splenomegaly. Multiple pathological mechanisms (e.g., circulating cytokines and genetic alterations, such as JAKV617F mutation) have been implicated in the etiology of MF, but the molecular mechanism causing resistance to JAK2V617F inhibitor therapy remains unknown. Among MF patients who were treated with the JAK inhibitor ruxolitinib, we compared noncoding RNA profiles of ruxolitinib therapy responders versus nonresponders and found miR-543 was significantly upregulated in nonresponders. We validated these findings by reverse transcription-quantitative PCR. in this same cohort, in 2 additional independent MF patient cohorts from the United States and Romania, and in a JAK2V617F mouse model of MF. Both in vitro and in vivo models were used to determine the underlying molecular mechanism of miR-543 in MF. Here, we demonstrate that miR-543 targets the dioxygenases ten-eleven translocation 1 (TET1) and 2 (TET2) in patients and in vitro, causing increased levels of global 5-methylcytosine, while decreasing the acetylation of histone 3, STAT3, and tumor protein p53. Mechanistically, we found that activation of STAT3 by JAKs epigenetically controls miR-543 expression via binding the promoter region of miR-543. Furthermore, miR-543 upregulation promotes the expression of genes related to drug metabolism, including CYP3A4, which is involved in ruxolitinib metabolism. Our findings suggest miR-543 as a potentially novel biomarker for the prognosis of MF patients with a high risk of treatment resistance and as a potentially new target for the development of new treatment options.

Noncoding RNA Profiles in Tobacco- and Alcohol-Associated Diseases.

Tobacco and alcohol are the leading environmental risk factors in the development of human diseases, such as cancer, cardiovascular disease, and liver injury. Despite the copious amount of research on this topic, by 2030, 8.3 million deaths are projected to occur worldwide due to tobacco use. The expression of noncoding RNAs, primarily microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), is modulated by tobacco and alcohol consumption. Drinking alcohol and smoking cigarettes can modulate the expression of miRNAs and lncRNAs through various signaling pathways, such as apoptosis, angiogenesis, and inflammatory pathways-primarily interleukin 6 (IL-6)/signal transducer and activator of transcription 3 (STAT3), which seems to play a major role in the development of diseases associated with these risk factors. Since they may be predictive and prognostic biomarkers, they can be used both as predictors of the response to therapy and as a targeted therapy. Further, circulating miRNAs might be valuable noninvasive tools that can be used to examine diseases that are related to the use of tobacco and alcohol. This review discusses the function of noncoding RNAs in cancer and other human tobacco- and alcohol-associated diseases.

MiR-223-5p works as an oncomiR in vulvar carcinoma by TP63 suppression.

MiR-223-5p has been previously mentioned to be associated with tumor metastasis in HPV negative vulvar carcinomas, such as in several other tumor types. In the present study, we hypothesized that this microRNA would be important in vulvar cancer carcinogenesis and progression. To investigate this, we artificially mimicked miR-223-5p expression in a cell line derived from lymph node metastasis of vulvar carcinoma (SW962) and performed in vitro assays. As results, lower cell proliferation (p < 0.01) and migration (p < 0.001) were observed when miR-223-5p was overexpressed. In contrast, increased invasive potential of these cells was verified (p < 0.004). In silico search indicated that miR-223-5p targets TP63, member of the TP53 family of proteins, largely described with importance in vulvar cancer. We experimentally demonstrated that this microRNA is capable to decrease levels of p63 at both mRNA and protein levels (p < 0.001, and p < 0.0001; respectively). Also, a significant inverse correlation was observed between miR-223-5p and p63 expressions in tumors from patients (p = 0.0365). Furthermore, low p63 protein expression was correlated with deeper tumor invasion (p = 0.0491) and lower patient overall survival (p = 0.0494). Our study points out miR-223-5p overexpression as a putative pathological mechanism of tumor invasion and a promising therapeutic target and highlights the importance of both miR-223-5p and p63 as prognostic factors in vulvar cancer. Also, it is plausible that the evaluation of p63 expression in vulvar cancer at the biopsy level may bring important contribution on prognostic establishment and in elaborating better surgical approaches for vulvar cancer patients.