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Identification of ALDH6A1 as a Potential Signature in Hepatocellular Carcinoma via Quantitative Profiling of the Mitochondrial Proteome

ABSTRACT: Various liver diseases, including hepatocellular carcinoma (HCC), have been linked to mitochondrial dysfunction, a condition characterized by abnormal levels of nitric oxide (NO) and reactive oxygen species (ROS). In this study, we subjected the human liver mitochondrial proteome to an extensive quantitative proteomic profiling analysis and molecular characterization to identify potential signatures indicative of cancer cell growth and progression. A sequential proteomic analysis identified 2452 mitochondrial proteins, of which 1464 and 2010 were classified as normal and HCC mitochondrial proteins, respectively, with 1022 overlaps. Further metabolic mapping of the HCC mitochondrial proteins narrowed our biological characterization to four proteins, namely ALDH4A1, LRPPRC, ATP5C1 and ALDH6A1. The latter protein, a mitochondrial methylmalonate semialdehyde dehydrogenase (ALDH6A1), was most strongly suppressed in HCC tumor regions (~10-fold decrease) and was predicted to present in plasma. Accordingly, we selected ALDH6A1 for a functional analysis. Interestingly, much lower NO levels were detected in both HCC tumor regions and an ALDH6A1-overexpression (O/E) cell line than in control (Hep3B) cells and could be restored by treatment with S-nitroso-N-acetyl-penicillamine. In contrast, ALDH6A1-O/E cells exhibited an approximately 50% increase in ROS levels and decreased lactate levels relative to control cells. Propidium iodine staining suggested that the abnormal decrease in NO and increase in ROS could be caused by depolarization of the mitochondrial membrane potential (ΔΨ). We propose that an attenuated ALDH6A1 level may subsequently promote uncontrolled cell growth and proliferation, act as a signature for assessing HCC progression and treatment responses.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Liver

SUBMITTER: Heon Shin

LAB HEAD: Young-Ki Paik

PROVIDER: PXD014252 | Pride | 2020-01-29

REPOSITORIES: Pride

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Identification of ALDH6A1 as a Potential Molecular Signature in Hepatocellular Carcinoma via Quantitative Profiling of the Mitochondrial Proteome.

Shin Heon H Cha Hyun-Jeong HJ Lee Min Jung MJ Na Keun K Park Donha D Kim Chae-Yeon CY Han Dai Hoon DH Kim Hoguen H Paik Young-Ki YK

Journal of proteome research 20200310 4

Various liver diseases, including hepatocellular carcinoma (HCC), have been linked to mitochondrial dysfunction, reduction of reactive oxygen species (ROS), and elevation of nitric oxide (NO). In this study, we subjected the human liver mitochondrial proteome to extensive quantitative proteomic profiling analysis and molecular characterization to identify potential signatures indicative of cancer cell growth and progression. Sequential proteomic analysis identified 2452 mitochondrial proteins, o ...[more]

PMID: 31985234

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Project description:Although disruption of mitochondrial function has been associated with energetic deregulation in cancer, the chronological changes in mitochondria during cancer development remain unclear. With the aim to assess the role of mitochondria throughout cancer development, we analyzed samples chronologically obtained from induced hepatocellular carcinoma (HCC) in rats. In our analyses, we integrated mitochondrial proteomic data, mitochondrial metabolomic data and nuclear genome transcriptomic data. We used pathway over-representation and weighted gene co-expression network analysis (WGCNA) to integrate expression profiles of genes, miRNAs, proteins and metabolite levels throughout HCC development. Our results show that mitochondria are dynamic organelles presenting specific modifications in different stages of HCC development. For carcinogenesis, a modified resistant hepatocyte model was used. Rats were initiated with diethylnitrosamine (DEN) (200 mg/kg of body weight) at day 0. Then, 2-acetylaminofluorene (AAF) was administered (20 mg/kg per dose) at days 7, 8 and 9, followed by 3/5 partial hepatectomy (PH) at day 10. Three control groups of non-treated animals were sacrificed by exsanguination on the first day and at 9 and 18 months after the beginning of the experiment. Treated animals were sacrificed at 1, 7, 11 and 16 days and at 1, 9 and 18 months. Their livers were excised, washed in physiological saline solution, frozen with liquid nitrogen in 2-methyl butane and stored at -80°C. Once selected and separately collected nodular, tumoral and its adjacent tissues, total RNA was isolated using TriPureIsolation Reagent (Roche) according to the manufacturer’s protocol. The microarray analysis was performed using GeneChip Rat Exon 1.0 ST Arrays. Four replicas for each condition and controls were analyzed. This created 11 pairwise contrasts for the differential expression analysis. We grouped all evaluated conditions in three categories: i) early stages, including samples obtained since day one until one month after treatment, these were compared against rats without treatment sacrificed the first day; ii) tumor, nodular and its adjacent tissues obtained from nine months rats were compared against rats without treatment of the same age; and iii) tumor and its adjacent tissues obtained from eighteen months rats were compared against rats without treatment of the same age.

			Action	DRS
	20140424_Mito_N1.mgf	Mgf
	20140424_Mito_N1.mzid.gz	Mzid
	20140424_Mito_N1.raw	Raw
	20140424_Mito_N2.mgf	Mgf
	20140424_Mito_N2.mzid.gz	Mzid