Dysregulated microRNAs (miRNAs) are involved in carcinoma progression, metastasis, and poor prognosis. We demonstrated that in nasopharyngeal carcinoma (NPC), transactivated MIR106A-5p promotes a malignant phenotype by functioning as a macroautophagy/autophagy suppressor by targeting BTG3 (BTG anti-proliferation factor 3) and activating autophagy-regulating MAPK signaling. MIR106A-5p expression was markedly increased in NPC cases based on quantitative real-time PCR, miRNA microarray, and TCGA database analysis findings. Moreover, MIR106A-5p was correlated with advanced stage, recurrence, and poor clinical outcomes in NPC patients. In addition to three-dimensional cell culture assays, zebrafish and BALB/c mouse tumor models revealed that overexpressed MIR106A-5p targeted BTG3 and accelerated the NPC malignant phenotype by inhibiting autophagy. BTG3 promoted autophagy, and its expression was correlated with poor prognosis in NPC. Attenuation of autophagy, mediated by the MIR106A-5p-BTG3 axis, occurred because of MAPK pathway activation. MIR106A-5p overexpression in NPC was due to increased transactivation by EGR1 and SOX9. Our findings may lead to novel insights into the pathogenesis of NPC.
Microcystin-leucine-arginine (MC-LR) has been implicated as a potential environmental factor in Alzheimer's disease because of its potent inhibition of protein phosphatase 2A (PP2A) activity, but experimental evidence to support its detailed neurotoxic effects and their underlying mechanisms has been lacking. The present study investigated the role of PP2A catalytic subunit (PP2Ac) demethylation and its link with glycogen synthase kinase-3β (GSK)-3β in tau hyperphosphorylation induced by MC-LR. The results showed that MC-LR treatment significantly increased demethylation of PP2Ac, with a concomitant increase in GSK-3β phosphorylation at Ser9 resulting in elevated tau hyperphosphorylation at PP2A-favorable sites in SH-SY5Y cells and rat hippocampus. Coimmunoprecipitation experiments showed that MC-LR treatment dissociated PP2Ac from Bα, making it incompetent in binding tau, thus causing tau hyperphosphorylation. Moreover, we found that inhibition of PP2A resulted in an increase in phosphorylation of GSK-3β at Ser9 and a decrease in GSK-3β activity, which further promoted demethylation of PP2Ac induced by MC-LR. These findings suggest a scenario in which MC-LR-mediated demethylation of PP2Ac is associated with GSK-3β phosphorylation at Ser9 and contributes to dissociation of Bα from PP2Ac, which would result in Bα degradation and disruption of PP2A/Bα-tau interactions, thus promoting tau hyperphosphorylation and paired helical filaments-tau accumulation and, consequently, axonal degeneration and cell death.
Nasopharyngeal carcinoma (NPC) is an aggressive malignancy that occurs on the top and sidewall of the nasopharynx cavity mostly in young and middle-aged adults. 1 According to a previous report, there are roughly 80 000 new cases in China every year while the total incidence accounts for 80% of the cases reported worldwide. 2 In particular, it has been demonstrated that cervical lymph node metastasis has already appeared in 75%-90% of patients at the time of initial diagnosis, 3 which is different from other head and neck squamous cell carcinoma (HNSCC). Generally, once metastasis occurs, the 5-year survival rate is 25%-30%. 4 However, it is still not clear which key components and
Microcystin‐leucine‐arginine (MC‐LR) is a toxin secreted by freshwater cyanobacteria that is considered a potential environmental risk factor for Alzheimer's disease (AD). A previous study indicated that tau protein hyperphosphorylation via protein phosphatase 2A (PP2A) and GSK‐3β inhibition was the mechanism by which MC‐LR induces neurotoxicity; however, how MC‐LR‐induced neurotoxicity can be effectively prevented remains unclear. In this study, the reversal effect of metformin on MC‐LR‐induced neurotoxicity was investigated. The results showed that metformin effectively prevented tau hyperphosphorylation at Ser202 caused by MC‐LR through PP2A and GSK‐3b activity. The effect of metformin on PP2A activity was dependent on the inhibition of mTOR in MC‐LR‐treated SH‐SY5Y cells. Metformin prevented spatial memory deficits in rats caused by intrahippocampal MC‐LR administration. In sum, the results suggested that metformin can ameliorate the MC‐LR–induced AD‐like phenotype by preventing tau phosphorylation at Ser202, which was mainly mediated by mTOR‐dependent PP2A and GSK‐3β activation.
The Forkhead-box (FOX) transcription factors, as one of the largest gene families in humans, play key roles in cancer. Although studies have suggested that several FOX transcription factors have a significant impact on cancer, the functions of most of the FOX genes in cancer remain elusive. In the study, the expression of 43 FOX genes in 63 kinds of cancer diseases (including many subtypes of same cancer) and in response to 60 chemical substances was obtained from the Gene Expression Atlas database of the European Bioinformatics Institute. Based on the high degree of overlap in FOXO family members differentially expressed in various cancers and their particular responses to chemotherapeutic drugs, our data disclosed the FOX genes that played an important role in the development and progression of cancer. More importantly, we predicted the role of one or several combinatorial FOX genes in the diagnosis and prognostic assessment of a specific cancer and evaluated the potential of a certain anticancer drug therapy for this type of cancer by integrating patterns of FOX genes expression with anticancer drugs sensitivity.
Nasopharyngeal carcinoma (NPC), the most frequent reason for treatment failure in head and neck tumors, has the greatest incidence of distant metastases. Increased vascular permeability facilitates metastasis. Exosomal microRNAs (miRNAs) have been implicated in the development of the premetastatic niche and are emerging as prospective biomarkers in cancer patients. We discovered that a higher level of miR‐455 was connected to a larger propensity for NPC metastasis based on deep sequencing and RT‐qPCR. We found that hypoxia promoted NPC exosomes release and increased miR‐455 expression in a way that was hypoxia‐inducible factor 1‐alpha (HIF‐1α) dependent. Exosomes from NPC cells with high levels of miR‐455 were found to specifically target zonula occludens 1 (ZO‐1), increasing the permeability of endothelial monolayers in vitro vascular permeability and transendothelial invasion experiments. Additional in vivo studies showed that zebrafish with sustained miR‐455‐overexpressing NPC cell xenografts displayed increased tumor cell mass throughout the body. In vivo, zebrafish vascular tight junction integrity was disrupted by exosomes produced by NPC cells with elevated miR‐455 expression. Mice‐bearing xenografts further supported the finding that exosomes containing miR‐455 might reduce ZO‐1 expression in addition to promote NPC cell growth. These findings suggest that in a hypoxic microenvironment, exosomal miR‐455 released by NPC cells enhances vascular permeability and promotes metastasis by targeting ZO‐1. The HIF‐1α‐miR‐455‐ZO‐1 signaling pathway may be a promising predictor and potential therapeutic target for NPC with metastasis.
Obesity is a prominent risk factor for certain types of tumor progression. Adipocytes within tumor stroma contribute to reshaping tumor microenvironment (TME) and the metabolism and metastasis of tumors through the production of cytokines and adipokines. However, the crosstalk between adipocytes and tumor cells remains a major gap in this field. Known as a subtype of selective autophagy, lipophagy is thought to contribute to lipid metabolism by breaking down intracellular lipid droplets (LDs) and generating free fatty acids (FAs). The metastatic potential of cancer cells closely correlates with the lipid degradation mechanisms, which are required for energy generation, signal transduction, and biosynthesis of membranes. Here, we discuss the recent advance in the understanding of lipophagy with tumor lipid metabolism and review current studies on the roles of lipoghagy in the metastasis of certain human malignancies. Additionally, the novel candidate drugs targeting lipophagy are integrated for effective treatment strategies.
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