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Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways.

ABSTRACT: Mitochondrial morphology is dynamically remodeled by fusion and fission in cells, and dysregulation of this process is closely implicated in tumorigenesis. However, the mechanism by which mitochondrial dynamics influence cancer cell survival is considerably less clear, especially in hepatocellular carcinoma (HCC). In this study, we systematically investigated the alteration of mitochondrial dynamics and its functional role in the regulation of autophagy and HCC cell survival. Furthermore, the underlying molecular mechanisms and therapeutic application were explored in depth. Mitochondrial fission was frequently upregulated in HCC tissues mainly due to an elevated expression ratio of DNM1L to MFN1, which significantly contributed to poor prognosis of HCC patients. Increased mitochondrial fission by forced expression of DNM1L or knockdown of MFN1 promoted the survival of HCC cells both in vitro and in vivo mainly by facilitating autophagy and inhibiting mitochondria-dependent apoptosis. We further demonstrated that the survival-promoting role of increased mitochondrial fission was mediated via elevated ROS production and subsequent activation of AKT, which facilitated MDM2-mediated TP53 degradation, and NFKBIA- and IKK-mediated transcriptional activity of NFKB in HCC cells. Also, a crosstalk between TP53 and NFKB pathways was involved in the regulation of mitochondrial fission-mediated cell survival. Moreover, treatment with mitochondrial division inhibitor-1 significantly suppressed tumor growth in an in vivo xenograft nude mice model. Our findings demonstrate that increased mitochondrial fission plays a critical role in regulation of HCC cell survival, which provides a strong evidence for this process as drug target in HCC treatment.

SUBMITTER: Huang Q

PROVIDER: S-EPMC4922447 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways.

Huang Qichao Q Zhan Lei L Cao Haiyan H Li Jibin J Lyu Yinghua Y Guo Xu X Zhang Jing J Ji Lele L Ren Tingting T An Jiaze J Liu Bingrong B Nie Yongzhan Y Xing Jinliang J

Autophagy 20160428 6

Mitochondrial morphology is dynamically remodeled by fusion and fission in cells, and dysregulation of this process is closely implicated in tumorigenesis. However, the mechanism by which mitochondrial dynamics influence cancer cell survival is considerably less clear, especially in hepatocellular carcinoma (HCC). In this study, we systematically investigated the alteration of mitochondrial dynamics and its functional role in the regulation of autophagy and HCC cell survival. Furthermore, the un ...[more]

PMID: 27124102

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Project description:BACKGROUND:Ankylosing spondylitis (AS) results from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the heritability of AS. METHODS:Using a candidate gene approach in this case-control study, 51 mainly functional single nucleotide polymorphisms (SNPs) in genes regulating inflammation were assessed in 709 patients with AS and 795 controls. Data on the patients with AS were obtained from the DANBIO registry where patients from all of Denmark are monitored in routine care during treatment with conventional and biologic disease modifying anti-rheumatic drugs (bDMARDs). The results were analyzed using logistic regression (adjusted for age and sex). RESULTS:Nine polymorphisms were associated with risk of AS (p?<?0.05). The polymorphisms were in genes regulating a: the TNF-? pathway (TNF -308 G?>?A (rs1800629), and?-?238 G?>?A (rs361525); TNFRSF1A -609 G?>?T (rs4149570), and PTPN22 1858 G?>?A (rs2476601)), b: the IL23/IL17 pathway (IL23R G?>?A (rs11209026), and IL18-137 G?>?C (rs187238)), or c: the NFkB pathway (TLR1 743 T?>?C (rs4833095), TLR4 T?>?C (rs1554973), and LY96-1625 C?>?G (rs11465996)). After Bonferroni correction the homozygous variant genotype of TLR1 743 T?>?C (rs4833095) (odds ratios (OR): 2.59, 95% confidence interval (CI): 1.48-4.51, p?=?0.04), and TNFRSF1A -609 G?>?T (rs4149570) (OR: 1.79, 95% CI: 1.31-2.41, p?=?0.01) were associated with increased risk of AS and the combined homozygous and heterozygous variant genotypes of TNF -308 G?>?A (rs1800629) (OR: 0.56, 95% CI: 0.44-0.72, p?=?0.0002) were associated with reduced risk of AS. CONCLUSION:We replicated associations between AS and the polymorphisms in TNF (rs1800629), TNFRSF1A (rs4149570), and IL23R (rs11209026). Furthermore, we identified novel risk loci in TNF (rs361525), IL18 (rs187238), TLR1 (rs4833095), TLR4 (rs1554973), and LY96 (rs11465996) that need validation in independent cohorts. The results suggest that genetically determined high activity of the TNF-?, IL23/IL17, and NFkB pathways increase risk of AS.

Dataset Information

Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways.

Publications

Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways.

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