Amplification of 1q is one of the most frequent chromosomal alterations in human hepatocellular carcinoma (HCC). In this study we identified and characterized a novel oncogene, Maelstrom (MAEL), at 1q24. Amplification and overexpression of MAEL was frequently detected in HCCs and significantly associated with HCC recurrence (P 5 0.031) and poor outcome (P 5 0.001). Functional study demonstrated that MAEL promoted cell growth, cell migration, and tumor formation in nude mice, all of which were effectively inhibited when MAEL was silenced with short hairpin RNA (shRNAs). Further study found that MAEL enhanced AKT activity with subsequent GSK-3b phosphorylation and Snail stabilization, finally inducing epithelial-mesenchymal transition (EMT) and promoting tumor invasion and metastasis. In addition, MAEL up-regulated various stemness-related genes, multidrug resistance genes, and cancer stem cell (CSC) surface markers at the messenger RNA (mRNA) level. Functional study demonstrated that overexpression of MAEL increased self-renewal, chemoresistance, and tumor metastasis. Conclusion: MAEL is an oncogene that plays an important role in the development and progression of HCC by inducing EMT and enhancing the stemness of HCC. (HEPA-TOLOGY 2014;59:531-543) H epatocellular carcinoma (HCC) is the fifth most common cancer and ranks as the third leading cause of cancer-related deaths in the world. 1 It is believed that HCC pathogenesis is a longterm progressive process involving the accumulation of multiple genetic and epigenetic alterations. 2 Amplification of the long arm of chromosome 1 has been detected in 58%-78% of primary HCC cases, suggesting that one or more oncogenes within the amplified region play a critical role in HCC development. 3,4 Our previous work had demonstrated that CHD1L at 1q21 plays a critical oncogenic role in the development and progression of HCC. Overexpression of CHD1L promotes cell proliferation, 5 induces tumor metastasis by way of epithelial-to-mesenchymal transition (EMT), 6 sustains cell survival, and increases drug resistance by inhibiting Nur77-mediated apoptosis. 7 Recently, we performed an integrative RNA sequencing (RNA-Seq) to identify differentially expressed genes between three pairs of clinical samples of HCC and their adjacent nontumor tissues. 8 Overexpression of Maelstrom (MAEL) at 1q24 was observed in all three HCC tumor tissues compared with their matched nontumor counterparts.The MAEL gene was initially identified in Drosophila 9 and is required for spermatogenesis and meiosis. 10 The human MAEL protein contains a high mobility group (HMG) domain in its N-terminal segment that is known to mediate DNA binding and a novel MAEL-specific domain in the C-terminal segment. 11
Trimethylamine N-oxide (TMAO) is produced from the phosphatidylcholine metabolism of gut flora and acts as a risk factor of cardiovascular disease.However, the underlying mechanisms for its proatherogenic action remain unclear.This study aimed to observe the effect of TMAO on endothelial cell pyroptosis and explore the underlying mechanisms. Our results showed that TMAO promoted the progression of atherosclerotic lesions in apolipoprotein E-deficient (apoE −/− ) mice fed a high-fat diet. Pyroptosis and succinate dehydrogenase complex subunit B (SDHB) upregulation were detected in the vascular endothelial cells of apoE −/− mice and in cultured human umbilical vein endothelial cells (HUVECs) treated with TMAO. Overexpression of SDHB in HUVECs enhanced pyroptosis and impaired mitochondria and high reactive oxygen species (ROS) level. Pyroptosis in the SDHB overexpression of endothelial cells was inhibited by the ROS scavenger NAC. In summary, TMAO promotes vascular endothelial cell pyroptosis via ROS induced through SDHB upregulation, thereby contributing to the progression of atherosclerotic lesions.
ObjectiveUsing whole genome sequencing, we identified gene amplification of solute carrier family 12 member 5 (SLC12A5) located at 20q13.12 in colorectal cancer (CRC). We analysed its amplification, overexpression, biological effects and prognostic significance in CRC.DesignSLC12A5 amplification status was evaluated by fluorescence in situ hybridisation (FISH). The effects of SLC12A5 re-expression or knockdown were determined in proliferation, apoptosis, invasion and metastasis assays. SLC12A5 target genes and related pathways were identified by reporter activity and cDNA microarray analyses. Clinical impact of SLC12A5 overexpression was assessed in 195 patients with CRC.ResultsAmplification of SLC12A5 was verified in 78 out of 191 (40.8%) patients with primary CRC by FISH, which was positively correlated with its protein overexpression (p<0.001). Biofunctional investigation of SLC12A5 revealed that SLC12A5 significantly increased cell proliferation, G1-S cell cycle transition, invasion/migration abilities, but suppressed apoptosis in vitro and promoted xenograft tumour growth as well as lung metastasis in vivo. The antiapoptosis effect by SLC12A5 was mediated through inhibiting apoptosis-inducing factor and endonuclease G-dependent apoptotic signalling pathway; and the pro-metastasis role was by regulating key elements of the matrix architecture, including matrix metallopeptidase and fibronectin. After a median follow-up of 50.16 months, multivariate analysis revealed that patients with SLC12A5 protein overexpression had a significant decrease in overall survival. Kaplan–Meier survival curves showed that SLC12A5 overexpression was significantly associated with shortened survival in patients with CRC.ConclusionsSLC12A5 plays a pivotal oncogenic role in colorectal carcinogenesis; its overexpression is an independent prognostic factor of patients with CRC.
Nasopharyngeal carcinoma is an Epstein-Barr Virus (EBV) associated malignancy which is highly prevalent in Southeast Asia. EBV-related antibodies have been widely used as screening markers for early nasopharyngeal carcinoma (NPC) detection. However, due to its low positive predictive rate, it is essential to develop new biomarkers to facilitate NPC early diagnosis or triage EBV serological high-risk individuals to improve the chance of NPC early detection. BART microRNAs, which are encoded by BamHI region of EBV, were reported to be abundant in NPC and have potential value in early diagnosis of NPC. Here, we quantified circulating level of 17 BART microRNAs in discovery stage based on previous microarray and sequencing data and, in particular, BART 2-5p, the sole candidate whose area under curve (AUC) was higher than 0.8, has been chosen for further study. In validation stage, the sensitivity, specificity and AUC of BART 2-5p was 93.9%, 89.8%, 0.972 (95%CI: 0.954-0.989), respectively, in Cohort 1 constituted by NPC patients and controls from Hong Kong. For validation Cohort 2 consisting of patients and controls from Guangzhou, the sensitivity, specificity and AUC was 94.2%, 83.5%, 0.959 (95%CI: 0.939-0.980), respectively. To evaluate its ability to distinguish preclinical NPC patients, we established a nested case-control study with serum samples prospectively collected from 22 NPC patients prior to their clinical diagnosis and 88 matched healthy high-risk controls in a screening trial. The sensitivity and specificity were 90.9% and 54.5%. Collectively, EBV microRNA BART2-5p may be a valuable biomarker for early detection of NPC.
Distant metastasis remains the major failure of nasopharyngeal carcinoma (NPC). In this study, the roles of chemokine C-C motif ligand 2 (CCL2), and its receptor chemokine C-C motif receptor type 2 (CCR2) on NPC metastasis were investigated. Serum CCL2 and CCL2/CCR2 expression level were remarkably increased in NPC patients compared to non-tumor patients by ELISA and IHC analyses. High expressions of CCL2/CCR2 were significantly associated with NPC metastasis and poor overall survival (OS). High expression of CCR2 is an independent adverse prognostic factor of OS and distant metastasis free survival (DMFS). Overexpressions of CCL2 and CCR2 were detected in high-metastatic NPC cell lines. Upregulating CCL2 and CCR2 respectively in low-metastatic NPC cell lines could promote cell migration and invasion, and exogenous CCL2 enhanced the motility in CCR2-overexpressing cells. On the other hand, downregulating CCL2 and CCR2 respectively in high-metastatic NPC cell lines by shRNA could decrease cell migration and invasion. However, exogenous CCL2 could not rescue the weaken ability of motility of CCR2-silencing cells. In nude mouse model, distant metastasis was significantly facilitated in either CCL2-overexpressing or CCR2-overexpressing groups, which was more obvious in CCR2-overexpressing group. Also, distant metastasis was considerably inhibited in either CCL2-silencing or CCR2-silencing groups. Dual overexpression of CCL2/CCR2 could activate extracellular signal-regulated kinase (ERK1/2) signaling pathway, which sequentially induced matrix metalloproteinase (MMP) 2 and 9 upregulations in the downstream. In conclusion, CCL2-CCR2 axis could promote NPC metastasis by activating ERK1/2-MMP2/9 pathway. This study helps to develop novel therapeutic targets for distant metastasis in NPC.
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