Abstract
Background: Mitophagy is correlated with tumor initiation and development of malignancy. However, HCC heterogeneity with reference to mitophagy has yet not been systematically explored. Materials and Methods: Mitophagy-related, glycolysis-related, and cholesterol biosynthesis-related gene sets were obtained from the Reactome database. Mitophagy-related and metabolism-related subtypes were identified using the ConsensusClusterPlus algorithm. Univariate Cox regression was analysis was performed to identify prognosis-related mitophagy regulators. Principal component analysis (PCA) was used to create composite measures of the prognosis-related mitophagy regulators (mitophagyscore). Individuals with a mitophagyscore higher or lower than the median value were classified in high- or low-risk groups. Kaplan-Meier survival and ROC curve analyses were utilized to evaluate the prognostic value of the mitophagyscore. The nomogram and calibration curves were plotted using the“rms” R package. The package “limma” was used for differential gene expression analysis. Differentially expressed genes (DEGs) between high- and low-risk groups were used as queries in the CMap database. R package “pRRophetic” and Genomics of Drug Sensitivity in Cancer (GDSC) database were used to determine the sensitivity of 21 previously reported anti-HCC drugs. Results: Three distinct HCC subtypes with different mitophagic accumulation (low, high, and intermediate mitophagy subtypes) were identified. High mitophagy subtype had the worst outcome and highest glycolysis level. The lowest degree of hypoxia and highest cholesterol biosynthesis was observed in the low mitophagy subtype; oncogenic dedifferentiation level in the intermediate mitophagy subtype was the lowest. Mitophagyscore could serve as a novel prognostic indicator for HCC.High-risk patients had a poorer prognosis (log-rank test, p < 0.001). The area under the ROC curve for mitophagyscore in 1-year survival was 0.77 in the TCGA cohort and 0.75 in the ICGC cohort. Nine candidate small molecules which were potential drugs for HCC treatment were identified from the CMap database. A decline in the sensitivity towards 21 anti-HCC drugs was observed in low-risk patients by GDSC database. We also identified a novel key gene, SPP1, which was highly associated with different mitophagic subtypes. Conclusion: Based on bioinformatic analyses, we systematically examined the HCC heterogeneity with reference to mitophagy and observed three distinct HCC subtypes having different prognoses and metabolic patterns.
Highlights
Hepatocellular carcinoma (HCC), a highly heterogeneous solid malignancy, is the third leading cause of cancer-related deaths, worldwide
We separately investigated the levels of expression of mitophagy regulators in The Cancer Genome Atlas (TCGA)-LIHC and International Cancer Genome Consortium (ICGC)-LIRI-JP cohorts (Figure 1A, B)
Compared with normal liver tissues, PINK1 and MFN2 showed a distinctly higher proportion of copy number alterations and 13 mitophagy regulators showed a higher proportion of gain in CNVs (e.g. TOMM20 and MLN1) (Figure 1D)
Summary
Hepatocellular carcinoma (HCC), a highly heterogeneous solid malignancy, is the third leading cause of cancer-related deaths, worldwide. A special form of autophagy, mitophagy, is a mechanism for mitochondrial quality control. Defective, or unfunctional mitochondria are identified by the mitophagic machinery and subsequently degraded in the lysosome (VaraPerez et al, 2019).The PINK1/Parkin pathway is among the most investigated pathway in mitophagy. The presenilinassociated rhomboid-like (PARL) proteins cleave PINK1 protein and target it for degradation to the mitochondrial proteasome. (Jin et al, 2010), (Lopez Domenech et al, 2018), (Wang et al, 2011) PINK1 accumulation promotes the E3 ubiquitin ligase activity of Parkin by the phosphorylation of serine 65 residue of the ubiquitin-like domain of Parkin. P62 and OPTN (autophagy cargo adaptors) recognize the polyubiquitylation of mitochondrial proteins and the autophagic machinery degrades the complex formed by the interaction of mitochondrial proteins and LC3. HCC heterogeneity with reference to mitophagy has yet not been systematically explored
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
