Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis.

BACKGROUND: The identification of novel targets for recovering sorafenib resistance is pivotal for Hepatocellular carcinoma (HCC) patients. Mitophagy is the programmed degradation of mitochondria, and is likely involved in drug resistance of cancer cells. Here, we identified hyperactivated mitophagy is essential for sorafenib resistance, and the mitophagy core regulator gene ATAD3A (ATPase family AAA domain containing 3A) was down regulated in hypoxia induced resistant HCC cells. Blocking mitophagy may restore the sorafenib sensitivity of these cells and provide a new treatment strategy for HCC patients. METHODS: Hypoxia induced sorafenib resistant cancer cells were established by culturing under 1% O2 with increasing drug treatment. RNA sequencing was conducted in transfecting LM3 cells with sh-ATAD3A lentivirus. Subsequent mechanistic studies were performed in HCC cell lines by manipulating ATAD3A expression isogenically where we evaluated drug sensitivity, molecular signaling events. In vivo study, we investigated the combined treatment effect of sorafenib and miR-210-5P antagomir. RESULTS: We found a hyperactivated mitophagy regulating by ATAD3A-PINK1/PARKIN axis in hypoxia induced sorafenib resistant HCC cells. Gain- and loss- of ATAD3A were related to hypoxia-induced mitophagy and sorafenib resistance. In addition, ATAD3A is a functional target of miR-210-5p and its oncogenic functions are likely mediated by increased miR-210-5P expression. miR-210-5P was upregulated under hypoxia and participated in regulating sorafenib resistance. In vivo xenograft assay showed that miR-210-5P antagomir combined with sorafenib abrogated the tumorigenic effect of ATAD3A down-regulation in mice. CONCLUSIONS: Loss of ATAD3A hyperactivates mitophagy which is a core event in hypoxia induced sorafenib resistance in HCC cells. Targeting miR-210-5P-ATAD3A axis is a novel therapeutic target for sorafenib-resistant HCC.

PCYT1A suppresses proliferation and migration via inhibiting mTORC1 pathway in lung adenocarcinoma.

Lung cancer is one of most common malignant cancer worldwide. It is emerging that PCYT1A, a rate-limiting enzyme required for the biosynthesis of phosphatidylcholine, is associated with cancer progression. However, the biological functions and underlying molecular mechanisms of PCYT1A in lung adenocarcinoma is still unknown. Here we found that PCYT1A suppressed lung adenocarcinoma cancer cell proliferation and migration. Mechanically, PCYT1A served as a novel negative regulator of mTORC1 signaling. PCYT1A knockdown enhanced the malignant proliferation and migration of lung adenocarcinoma cells by activating mTORC1. The promoting effects of PCYT1A silencing on cell proliferation and migration could be abolished when mTORC1 signaling was inhibited by rapamycin or RAPTOR depletion. Importantly, PCYT1A high expression predicted longer survival of lung cancer patients. The expression of PCYT1A was also negatively correlated with mTORC1 activation in the clinical lung cancer samples. We therefore reveal that PCYT1A suppresses proliferation and migration by inhibiting the mTORC1 signaling pathway in lung adenocarcinoma. PCYT1A shows as a potential promising biomarker in lung adenocarcinoma.

Gut microbiome associated with APC gene mutation in patients with intestinal adenomatous polyps.

Background: The 'adenoma-carcinoma sequence' is a well-recognized model of colorectal cancer (CRC) development. However, the interaction between gut microbiota and genetic variation in the initiation of CRC is not clear. Our study attempts to demonstrate the relationship between gut microbiota and host genetics in patients with intestinal adenomatous polyps. Method: The entire exon region of the APC gene was sequenced in 35 patients with pathologically diagnosed adenomatous polyps. Patients with highly pathogenic APC mutation were classified as the case group, while the others were classified as the control group. The patients'stool and serum samples were respectively collected for metagenomics and metabolomics measurements. Results: In the analysis of gut microbiome, there were three most important species, in which Fusobacterium_mortiferum was significantly increased while Faecalibacterium_prausnitzii and Bifidobacterium_pseudocatenulatum were significantly decreased in the case group. The significantly low abundance of the Photosynthesis pathway in patients with APC mutation was due to the low abundance of species Faecalibacterium_prausnitzii and Bifidobacterium_pseudocatenulatum. Moreover, there were two clusters of KEGG pathways correlated with two clusters of species characterized by Faecalibacterium_prausnitzii and Fusobacterium_mortiferum. As to serum metabolomics, the abundance of (R)-3-Hydroxybutyric acid and 2-Hydroxyphenethylamine were significantly higher in patients with APC mutation, while the abundance of 1-Aminocyclopropanecarboxylic acid,7-Ketocholesterol, DL-lactate, and L-Pyroglutamic acid were significantly higher in controlgroup. After analyzing the metabolome and microbiome data by sparCCmethod, we found that there was a significantly negative correlation between the abundance of Faecalibacterium_prausnitzii and Fusobacterium_mortiferum, and a significantly positive correlation between Faecalibacterium_prausnitzii abundance and the steroid hormone Hydrocortisone (Cortisol) in serum. Conclusions: Host's APC mutation was closely related to the changes of gut microbiota and serum metabolites, and some species of gut microbiome like Faecalibacterium_prausnitzii and Fusobacterium_mortiferum might have the potential to predict the development of CRC from intestinal adenomatous polyps.

Evaluation of Red Cell Distribution Width to Lymphocyte Ratio as Potential Biomarker for Detection of Colorectal Cancer.

BACKGROUND AND AIM: Colorectal cancer (CRC) is the third most lethal cancer globally. This study sought to determine the feasibility of using red cell distribution width-to-lymphocyte ratio (RLR) as a tool to facilitate CRC detection. METHODS: Seventy-eight healthy controls, 162 patients diagnosed with CRC, and 94 patients with colorectal polyps (CP) from June 2017 to October 2018 were retrospectively reviewed. Clinical data were obtained to analyze preoperative RLR level, and receiver operating characteristic (ROC) curve analysis was performed to estimate the potential role of RLR as a CRC biomarker. RESULTS: RLR was higher in patients with CRC than in healthy participants (P < 0.05). ROC analysis indicated that combined detection of RLR and CEA appears to be a more effective marker to distinguish among controls, CP, and CRC patients, yielding 56% sensitivity and 90% specificity. RLR levels were significantly greater in those who had more advanced TNM stages (P < 0.05) and patients with distant metastasis stages (P < 0.05). CONCLUSIONS: RLR might serve as a potential biomarker for CRC diagnosis.