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Prostate cancer (PCa) stands as one of the most prevalent malignancies in men, ranking as the fifth leading cancer-associated mortality. Castration-resistance metastatic phenotype acquisition is substantiated by reprogramming of cellular responses to oxidative stress damage, involving evading apoptosis by losing p53 and modulating canonical mitophagy. Understanding the molecular underpinnings of mitochondria-related PCa, dysregulated miR-141 and autophagy-modulating MAPK1/ERK2 in canonical mitophagy altered context of PCa cell line model (LNCaP (p53+/+) and PC3 (p53−/−)) can provide insights into potential therapeutic strategies. Utilising nanopore transcriptome sequencing, differential gene expression was analysed post miR-141 mimic/inhibitor modulation. MiR-141 upregulation enriched pathways associated with TAK1-JNK-c-Jun and MAPK activation. However, its inhibition prioritized non-immune pathways, emphasising lysosome biogenesis. Using DAPGreen (a microtubule-associated protein 1A/1B-light chain 3 (LC3) marker analogue), flow cytometry and live imaging demonstrated that miR-141 rescue amplified macroautophagy in p53+/+ cells, which diminished under starvation; conversely, in p53−/− cells, the rescue initially suppressed macroautophagy but enhanced it when combined with starvation. MAPK1 silencing revealed that MAPK1 had suppressive effect in p53+/+ cells, which was lost in p53−/− cells. Combined with starvation it resulted in macroautophagy upregulation in both cell lines. Mitophagy flux detected by MtPhagy and Lyso dyes demonstrated that miR-141 rescue amplified mitophagy under normal and starved conditions in p53+/+ cells, while in p53−/− cells, amplification only occurred during starvation. In both cell lines, starvation alone supressed mitophagy. MAPK1 had suppressive effect on mitophagy only during starvation, regardless of p53 status. Modifying miR-141 and MAPK1/ERK2 dynamic duality axis could present a potential therapeutic strategy. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) and their derived exosomes have shown potentials in the control of myocardial dysfunction. This study aimed to reveal the function of bone marrow (BM)-MSC-derived exosomes in sepsis-induced myocardial injury and the molecular mechanism. BM-MSC-derived exosomes were obtained and identified. A mouse model with sepsis was induced by cecalligation puncture (CLP) and treated with exosomes. The myocardial function of mice, the production of creatine kinase MB (CK-MB) and lactate dehydrogenase (LDH) in serum, the phosphorylation of a key myocardial contractility-related protein phospholamban (PLB), and the pathological changes in the myocardial tissues were examined. A microRNA (miRNA) microarray analysis was performed to examine the candidate miRNAs carried by the exosomes. Rescue experiments were conducted to validate the involvement of miR-141. CLP treatment led to sepsis and notably reduced the myocardial function in mice. Further treatment of BM-MSC-derived exosomes alleviated the CLP-induced myocardial impairment, production of CK-MB and LDH, and inflammatory infiltration and cell apoptosis in mouse myocardial tissues, and restored the PLB phosphorylation. miR-141 was the most upregulated miRNA in the myocardial tissues after exosome treatment. Downregulation of miR-141 blocked the myocardium-protective functions of the exosomes. miR-141 was found to bind to and suppress PTEN expression, which further enhanced the activity of β-catenin. This study suggested that BM-MSC derived exosomes ameliorates myocardial injury in septic mice through conveying miRNA-141 and regulating the PTEN/β-catenin axis, and exosomes may serve as promising tools for the management of myocardial injury induced by sepsis or other factors. [ABSTRACT FROM AUTHOR]

Background: Transmembrane-4-L-six-family-1 (TM4SF1) functions to regulate cell growth and mobility and TM4SF1 expression was upregulated in pancreatic cancer. This study further investigated the role of TM4SF1 in regulating pancreatic cancer epithelial-mesenchymal transition (EMT) and angiogenesis and the underlying molecular events. Methods: Tissue specimens were collected from 90 pancreatic cancer patients for immunohistochemical and qRT-PCR analysis of miR-141 and TM4SF1 levels, respectively. Pancreatic cancer cell lines were used for in vitro assays, while nude mice were used for the in vivo assay. Results: TM4SF1 expression was upregulated, whereas miR-141 expression was lost in pancreatic cancer tissues, both of which was associated with advanced clinicopathological features and poor survival of pancreatic cancer patients. Furthermore, miR-141 was able to target and reduce TM4SF1 expression in pancreatic cancer cells and miR-141 expression inhibited pancreatic cancer cell EMT in vitro and Matrigel plug angiogenesis and lung metastasis in nude mice. At the gene level, miR-141 directly targeted and reduced TM4SF1 expression and in turn induced E-cadherin expression and reduced VEGF-A expression by suppressing activation of the AKT signaling pathway. Conclusions: This study demonstrated that upregulated TM4SF1 and lost miR-141 expression were associated with advanced clinicopathological features and poor survival of pancreatic cancer patients. Lost miR-141 expression but induced TM4SF1 expression altered expression of VEGF-A and E-cadherin and promoted pancreatic cancer cell EMT and angiogenesis via the AKT signaling pathway, suggesting that targeting of miR-141 and TM4SF1 may be a potential therapeutic strategy to control pancreatic cancer. [ABSTRACT FROM AUTHOR]

Colon cancer, also known as colorectal carcinoma (CRC), remains to be one of the most mainsprings of cancer-produced deaths entire world. We planned to grab the role and possible biological cause of a long noncoding RNA, namely, small nucleolar RNA host gene 15 (SNHG15), in CRC. The mRNA level of SNHG15 in CRC tissues and cells was detected, followed by investigating the impacts of the depression of SNHG15 on CRC cell proliferation (viability and colony-forming), apoptosis, migration, and invasion. Moreover, the association between SNHG15 and miR-141 and the correlation between miR-141 and SIRT1 were also explored. Besides, the influences of dysregulated SNHG15 on the Wnt/β-catenin signal-related proteins were determined. SNHG15 was highly expressed in CRC tissues and cells. Depression of SNHG15 depressed proliferation, enhanced apoptosis, and repressed the migration and invasion of CRC cells. In addition, SNHG15 presented a downside tendency on regulating miR-141, and the miR-141 inhibitor dramatically changeover the impacts of SNHG15 depression on tumor growth and metastasis. Moreover, SIRT1 was verified as a functional target of miR-141 in CRC cells. Besides, the suppression of SNHG15 remarkably controlled activating the Wnt/β-catenin signals, which was reversed after inhibiting miR-141 at the same time. The investigated results in this research revealed that the increased expression of SNHG15 may enhance the process of CRC by acting as a ceRNA in regulating SIRT1 expression by sponging miR-141. Thus we propose that Wnt/β-catenin signals may be a downriver regulator in mediating the impacts of SNHG15 in CRC and SNHG15-miR-141-SIRT1 axis may pave a new sight in explaining the biological processes of CRC. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most aggressive brain tumor. Although miR-141 has been demonstrated to primarily function as a tumor suppressor in numerous malignancies, including glioblastoma, the mechanisms involved remain poorly understood. Here, it is shown that miR-141 is downregulated in glioblastoma cell lines and tissues and may exert its biological function via directly targeting myelin transcription factor 1-like (MYT1L). Using two glioblastoma cell lines that differ from each other by the functionality of DNA-dependent protein kinase (DNAPK), a functional involvement of DNAPK in the miR-141 tumor suppression network was observed. In M059K cells with a normal function of DNAPK, the enforced expression of miR-141 attenuated MYT1L expression and suppressed cell proliferation. Conversely, the inhibition of miR-141 expression promoted cell proliferation; however, in M059J cells with a loss-of-function DNAPK, miR-141 constitutively inhibited cell proliferation upon ectopic overexpression or inhibition. An overexpression of miR-141 suppressed M059J cell migration, while it had no effect on M059K. Furthermore, the ectopic expression of miR-141 induced an S-phase arrest in both cell lines, whereas the inhibition of miR-141 caused a G1 arrest in M059J and accelerated the S phase in M059K. An overexpression and suppression of miR-141 resulted in an aberrant expression of cell-cycle proteins, including p21. Moreover, MYT1L may be a transcription factor of p21 in p53-mutant cells, whereas DNAPK may function as a repressor of MYT1L. The findings revealed the crucial role of DNAPK in miR-141-mediated suppression of gliomagenesis and demonstrated that it may be a target molecule in miR-141-associated therapeutic interventions for glioblastoma. [ABSTRACT FROM AUTHOR]