Increased Drp1 promotes autophagy and ESCC progression by mtDNA stress mediated cGAS-STING pathway.

BACKGROUND: Mitochondrial dynamics homeostasis is important for cell metabolism, growth, proliferation, and immune responses. The critical GTPase for mitochondrial fission, Drp1 is frequently upregulated in many cancers and is closely implicated in tumorigenesis. However, the mechanism underling Drp1 to influence tumor progression is largely unknown, especially in esophageal squamous cell carcinoma (ESCC). METHODS: Immunohistochemistry was used to examine Drp1 and LC3B expression in tissues of ESCC patients. Autophagic vesicles were investigated by transmission electron microscopy. Fluorescent LC3B puncta and mitochondrial nucleoid were observed by fluorescent and confocal microscopy. Mitochondrial function was evaluated by mitochondrial membrane potential, ROS and ATP levels. Xenograft tumor model was performed in BALB/c nude mice to analyze the role of Drp1 on ESCC progression. RESULTS: We found that Drp1 high expression is correlated with poor overall survival of ESCC patients. Drp1 overexpression promotes cell proliferation and xenograft ESCC tumor growth by triggering autophagy. Furthermore, we demonstrated that Drp1 overexpression disturbs mitochondrial function and subsequent induces mitochondrial DNA (mtDNA) released into the cytosol thereby inducing cytosolic mtDNA stress. Mechanistically, cytosolic mtDNA activates the cGAS-STING pathway and facilitates autophagy, which promotes ESCC cancer growth. Moreover, mtDNA digestion with DNase I and autophagy inhibition with chloroquine attenuates the cGAS-STING pathway activation and ESCC cancer growth. CONCLUSIONS: Our finding reveals that Drp1 overexpression induces mitochondrial dysfunction and cytosolic mtDNA stress, which subsequently activates the cGAS-STING pathway, triggers autophagy and promotes ESCC progression.

Elevated TEFM expression promotes growth and metastasis through activation of ROS/ERK signaling in hepatocellular carcinoma.

TEFM (transcription elongation factor of mitochondria) has been identified as a novel nuclear-encoded transcription elongation factor in the transcription of mitochondrial genome. Our bioinformatics analysis of TCGA data revealed an aberrant over-expression of TEFM in hepatocellular carcinoma (HCC). We analyzed its biological effects and clinical significance in this malignancy. TEFM expression was analyzed by quantitative real-time PCR, western blot, and immunohistochemistry analysis in HCC tissues and cell lines. The effects of TEFM on HCC cell growth and metastasis were determined by cell proliferation, colony formation, flow cytometric cell cycle and apoptosis, migration, and invasion assays. TEFM expression was significantly increased in HCC tissues mainly caused by down-regulation of miR-194-5p. Its increased expression is correlated with poor prognosis of HCC patients. TEFM promoted HCC growth and metastasis both in vitro and in vivo by promoting G1-S cell transition, epithelial-to-mesenchymal transition (EMT), and suppressing cell apoptosis. Mechanistically, TEFM exerts its tumor growth and metastasis promoting effects at least partly through increasing ROS production and subsequently by activation of ERK signaling. Our study suggests that TEFM functions as a vital oncogene in promoting growth and metastasis in HCC and may contribute to the targeted therapy of HCC.

Long noncoding RNA LINC00662 promotes M2 macrophage polarization and hepatocellular carcinoma progression via activating Wnt/ß-catenin signaling.

Tumor-associated macrophages have important roles in hepatocellular carcinoma (HCC) initiation and progression. Long noncoding RNAs (lncRNAs) have also been reported to be involved in HCC. In this study, we explored how lncRNA LINC00662 may influence HCC progression through both tumor cell-dependent and macrophage-dependent mechanisms. LINC00662 was found to be upregulated in HCC, and high LINC00662 levels correlated with poor survival of HCC patients. LINC00662 upregulated WNT3A expression and secretion via competitively binding miR-15a, miR-16, and miR-107. Through inducing WNT3A secretion, LINC00662 activated Wnt/ß-catenin signaling in HCC cells in an autocrine manner and further promoted HCC cell proliferation, cell cycle, and tumor cell invasion, while repressing HCC cell apoptosis. In addition, acting through WNT3A secretion, LINC00662 activated Wnt/ß-catenin signaling in macrophages in a paracrine manner and further promoted M2 macrophage polarization. Via activating Wnt/ß-catenin signaling and M2 macrophages polarization, LINC00662 significantly promoted HCC tumor growth and metastasis in vivo. Hence, targeting LINC00662 may provide novel therapeutic strategy against HCC.

Danshen formula granule and salvianic acid A alleviate ethanol-induced neurotoxicity.

As a direct neurotoxin, ethanol exposure is associated with nerve damage and dysfunction of central nervous system (CNS) and induced obvious neurotoxicity by increasing the reactive oxygen species (ROS) production, activation of endogenous apoptotic as well as necrotic signals, and other molecular mechanisms. The previous studies had demonstrated that natural herbal medicine offers protective effectiveness on ethanol-induced nerve cell damage. Danshen and its extracts have been known to have an antioxidant property and neuroprotective effects. However, the protective effects of Danshen formula granule and salvianic acid A on ethanol-induced neurotoxicity remain unknown. In this study, we found that the Danshen formula granule and salvianic acid A significantly inhibited the ethanol-induced cell death, blocked LDH release, and reduced dendritic spine loss. Furthermore, the intracellular ROS, MDA production, and ethanol-induced apoptosis were significantly ameliorated with Danshen formula granule and salvianic acid A pretreatment by increasing the antioxidant enzymatic activity of CAT, SOD and GSH-Px, and inhibiting apoptotic pathways. In addition, Danshen formula granule and salvianic acid A pretreatment obviously inhibit the apoptotic pathways by regulating the protein expression of Bcl-2, Bax, and Caspase-3. In conclusion, our data demonstrated that the Danshen formula granule and salvianic acid A provide a significantly protective effectiveness against ethanol-induced neurotoxicity, which might be a potential therapeutic drug for ethanol-induced neurological disorders.