bims-resufa 2018-03-18 papers

Issue of 2018‒03‒18
two papers selected by
Josh Garlich
Medical College of Wisconsin

J Proteomics. 2018 Mar 07. pii: S1874-3919(18)30096-4. [Epub ahead of print]

Integrated omics profiling identifies hypoxia-regulated genes in HCT116 colon cancer cells.

Jeng-Ting Chen, Chien-Chun Liu, Jau-Song Yu, Hung-Hsuan Li, Ming-Chih Lai.

Hypoxia is associated with poor prognosis in most solid tumors due to its multiple effects on therapy resistance, angiogenesis, apoptotic resistance, and tumor invasion/metastasis. Here we used a comprehensive omics profiling to investigate hypoxia-regulated gene expression in HCT116 colon cancer cells. Quantitative analyses of proteome and secretome were performed in HCT116 cells cultured under hypoxic or normoxic conditions. A total of 5700 proteins were quantified in proteome analysis and 722 proteins were quantified in secretome analysis. Both datasets were combined with the transcriptome and translatome datasets for further analysis. Verification of candidate proteins/genes in this integrated omics analysis was performed using immunoblotting and quantitative real-time RT-PCR analyses. We also performed polysome profiling to assess changes in translational efficiency of hypoxia-induced genes. Notably, several genes were differently regulated at the transcriptional and translational levels in HCT116 cells during hypoxia. Bioinformatics analysis suggested that hypoxia regulates translation of genes involved in extracellular matrix organization, extracellular exosomes, and protein processing in endoplasmic reticulum. Aberrations in these metabolic pathways appear to be correlated with an increased risk of tumor invasion/metastasis.BIOLOGICAL SIGNIFICANCE: This study integrates transcriptome/translatome and proteome/secretome to analyze gene expression changes in human colon cancer cells under hypoxic conditions. Candidate proteins/genes in this integrated omics analysis were further validated by immunoblotting, quantitative real-time RT-PCR, and polysome profiling. The datasets would be useful to uncover the molecular mechanisms of hypoxia-induced gene regulation in colorectal cancer.

Keywords: Colorectal cancer; Hypoxia; Proteome; Secretome; Transcriptome; Translatome

DOI: https://doi.org/10.1016/j.jprot.2018.02.031

Life Sci. 2018 Mar 07. pii: S0024-3205(18)30122-X. [Epub ahead of print]

Heme oxygenase-1 protects liver against ischemia/reperfusion injury via phosphoglycerate mutase family member 5-mediated mitochondrial quality control.

Jeong-Min Hong, Sun-Mee Lee.

AIMS: Heme oxygenase-1 (HO-1), an endogenous cytoprotective enzyme, is reported that can be localized in mitochondria under stress, contributing to preserve mitochondrial function. Mitochondrial quality control (QC) is essential to cellular health and recovery linked with redox homeostasis. Recent studies reported that phosphoglycerate mutase family member (PGAM) 5, a mitochondria-resident phosphatase, plays critical role in mitochondrial homeostasis. Therefore, we aim to investigate cytoprotective mechanisms of HO-1 in I/R-induced hepatic injury focusing on mitochondrial QC associated with PGAM5 signaling.MAIN METHODS: Mice were subjected to 60 min of hepatic ischemia followed by 6 h reperfusion and were pretreated twice with hemin (HO-1 inducer, 30 mg/kg) or zinc protoporphyrin (ZnPP; HO-1 inhibitor, 10 mg/kg) 16 and 3 h before ischemia.
KEY FINDINGS: I/R increased hepatic and mitochondrial HO activity, which was augmented by hemin. I/R-induced hepatocellular and mitochondrial damages were attenuated by hemin and augmented by ZnPP. Meanwhile, I/R increased mitochondrial biogenesis, as evidenced by increased mitochondrial DNA contents and mitochondrial transcription factor A protein expression. Hemin augmented these results. I/R impaired mitophagy, as indicated by decreases in Parkin protein expression and the number of mitophagic vacuoles. These changes were attenuated by hemin. Hemin attenuated the I/R-induced increase in mitochondrial fission-related protein, dynamin-related protein 1, and the decrease in PGAM5 protein expression. Furthermore, PGAM5 siRNA abolished the effect of HO-1 on mitochondrial QC in HepG2 cells subjected to hypoxia/reoxygenation.
SIGNIFICANCE: Our findings suggest that HO-1 protects against I/R-induced hepatic injury via regulation of mitochondrial QC by PGAM5 signaling.

Keywords: Heme oxygenase-1; Ischemia/reperfusion; Mitochondrial quality control; Phosphoglycerate mutase family member 5

DOI: https://doi.org/10.1016/j.lfs.2018.03.017