Pan-cancer analysis identifies LPCATs family as a prognostic biomarker and validation of LPCAT4/WNT/ß-catenin/c-JUN/ACSL3 in hepatocellular carcinoma.

Lipid remodeling regulators are now being investigated as potential therapeutic targets for cancer therapy as a result of their involvement, which includes promoting cancer cells' adaptation to the restricted environment. Lysophosphatidylcholine acyltransferases (LPCATs, LPCAT1-4) are enzymes that regulate the remodeling of bio-membranes. The functions of these enzymes in cancer are largely unknown. In the current study, we found that genes belonging to the LPCAT family participated in tumor advancement and were strongly linked to dismal prognosis in many different malignancies. We constructed the LPCATs scores model and explored this model in pan-cancer. Malignant pathways in pan-cancer were positively related to LPCATs scores, and all pathways had strong links to the tumor microenvironment (TME). Multiple immune-associated features of the TME in pan-cancer were likewise associated with higher LPCATs scores. In addition, the LPCATs score functioned as a prognostic marker for immune checkpoint inhibitor (ICI) therapies in patients with cancer. LPCAT4 enhanced cell growth and cholesterol biosynthesis by up-regulating ACSL3 in hepatocellular carcinoma (HCC). WNT/ß-catenin/c-JUN signaling pathway mediated LPCAT4's regulation on ACSL3. These findings demonstrated that genes in the LPCAT family might be used as cancer immunotherapy and prognosis-related biomarkers. Specifically, LPCAT4 could be a treatment target of HCC.

IGF2BP3-induced activation of EIF5B contributes to progression of hepatocellular carcinoma cells.

In this study, we investigated the functional role of eukaryotic initiation factor 5B (EIF5B) in hepatocellular carcinoma (HCC) and the underlying mechanisms. Bioinformatics analysis demonstrated that the EIF5B transcript and protein levels as well as the EIF5Bcopy number were significantly higher in the HCC tissues compared with the non-cancerous liver tissues. Down-regulation of EIF5B significantly decreased proliferation and invasiveness of the HCC cells. Furthermore, EIF5B knockdown suppressed epithelial-mesenchymal transition (EMT) and the cancer stem cell (CSC) phenotype. Down-regulation of EIF5B also increased the sensitivity of HCC cells to 5-fluorouracil (5-FU). In the HCC cells, activation of the NF-kappa B signaling pathway and IkB phosphorylation was significantly reduced by EIF5B silencing. IGF2BP3 increased the stability of the EIF5B mRNA in an m6A-dependent manner. Our data suggested that EIF5B is a promising prognostic biomarker and therapeutic target in HCC.

circ_0001730 promotes proliferation and invasion via the miR-326/Wnt7B axis in glioma cells.

Aim: To study the role of circRNA (circ_0001730) in glioblastoma. Materials & methods: The interaction between circ_0001730 and miR-326 was confirmed by FISH, RNA pull down, RNA-binding protein immunoprecipitation and luciferase reporter assays. Cell proliferation and growth were determined by MTT, EdU and colony formation assays. Cell migration was assessed by the Boyden assay. Results: The levels of circ_0001730 were elevated in glioblastoma cell lines and tissues. circ_0001730 downregulation suppressed migration and proliferation in glioblastoma cells. SP1 bounds to the promoter of circ_0001730 host gene EPHB4 thereby increasing the expression of circ_0001730. circ_0001730 activated the Wnt/ß-catenin pathway via the miR-326/Wnt7B axis. Conclusion: circ_000173 promoted growth and invasion in glioblastoma cells via the miR-326/Wnt7B axis.

MicroRNA-224, negatively regulated by c-jun, inhibits growth and epithelial-to-mesenchymal transition phenotype via targeting ADAM17 in oral squamous cell carcinoma.

Abnormal expression of miR-224 has been reported to promote cancer progression. However, the role of miR-224 is seldom reported in oral squamous cell carcinoma (OSCC). We reported that miR-224 expression was significantly down-regulated in OSCC tissues and cell lines. Restoration of miR-224 decreased OSCC cell growth and invasion. In addition, luciferase and Western blot assays revealed that ADAM17 protein was a downstream target of miR-224. The overexpression of ADAM17 dismissed miR-224's effect on cell growth and invasion. We concluded that miR-224 inhibited OSCC cell growth and invasion through regulating ADAM17 expression. Subsequently, we revealed that c-jun directly bind to miR-224 promoter and decreased miR-224 expression. Taken together, these findings demonstrated that miR-224 may function as a tumour-suppressive microRNA in OSCC and suggested that miR-224 may be a potential therapeutic target for OSCC patients.

EVI1 promotes epithelial-to-mesenchymal transition, cancer stem cell features and chemo-/radioresistance in nasopharyngeal carcinoma.

BACKGROUND: Aberrant EVI1 expression is frequently reported in cancer studies; however, its role in nasopharyngeal carcinoma (NPC) has not been examined in detail. The aim of the present study is to investigate the involvement of EVI1 in progression and prognosis of NPC. METHODS: RT-PCR, immunohistochemistry and western blot assays were used to examine the expression of EVI1 in NPC tissues and cell lines. Fluorescence in situ hybridization assay was used to examine the amplification of EVI1 in NPC tissues. The biological effect of EVI1 was determined by both in vitro and in vivo studies. The dual-luciferase reporter assay was performed to confirm that EVI1 bind at E-cadherin andß-catenin promoters. The ChIP, EMSA, and coimmunoprecipitation combined with mass spectrometry assays were used to analyze the EVI1 regulated proteins. RESULTS: EVI1 expression level was up-regulated in NPC tissues and cell lines. EVI1 was amplificated in NPC tissues. We observed that EVI1 down-regulation decreased the cell proliferation and invasive capacity of NPC cells in vitro and in vivo. EVI1, snail, and HDAC1 formed a co-repressor complex to repress E-cadherin expression and ultimately contributed to epithelial mesenchymal transition (EMT) phenotype in NPC cells. In another way, EVI1 directly bound at ß-catenin promoter and activated its expression. ß-catenin mediated EVI1's function on cancer stem cells (CSCs) properties. EVI1 up-regulation predicted unfavorable prognosis and contributed to chemo/radio-resistance in NPC cells. Finally, we constructed arsenic trioxide-loaded nanoparticles (ALNPs) and revealed that ALNPs exerted anti-tumor effect in NPC cells. CONCLUSIONS: Our data indicated that EVI1 played an oncogenic role in NPC growth and metastasis and that EVI1 might serve as a novel molecular target for the treatment of NPC.

Meta-analysis of the relationship between excision repair cross-complementing Group 5 rs17655 gene polymorphism and head and neck cancer susceptibility.

BACKGROUND: Published studies have evaluated the association between excision repair cross-complementing Group 5 (ERCC5) rs17655 polymorphism and head and neck cancer (HNC) susceptibility. However, these studies showed inconsistent results. AIMS: The aim of this study was to get a more comprehensive estimation of this association. MATERIALS AND METHODS: Multiple databases were searched for the genetic association on the ERCC5 rs17655 polymorphism and HNC risk. Ten studies with a total of 3922 cases and 5871 controls were finally identified to be eligible studies in this meta-analysis. Odds ratio with 95% confidence intervals was used to assess the strength of association. RESULTS: Overall, this meta-analysis showed that there was no association between ERCC5 rs17655 polymorphism and HNC risk under all five genetic models. Further, no significant associations between the ERCC5 rs17655 polymorphism and HNC risk were found under the five genetic models in subgroup analyses based on the source of control. However, in stratified analyses by ethnicity, a significant association was found under the homozygous and recessive models in European. CONCLUSIONS: Our investigations demonstrate that genotypes for the ERCC5 rs17655 polymorphism may be not associated with overall cancer risk. In a subgroup meta-analysis, the results suggest that the ERCC5 rs17655 polymorphism is probably associated with HNC risk in European, but the results should be interpreted with caution for the low number of studies.

Direct targeting of MAPK8IP1 by miR-10a-5p is a major mechanism for gastric cancer metastasis.

MicroRNA (miRNA) are endogenous non-coding RNAs that suppress gene expression at the transcriptional, post-transcriptional or translational level by targeting the 3'-UTRs of specific mRNAs. miR-10a has been frequently reported to be aberrantly overexpressed in human tumors. In gastric cancer (GC), miR-10a has an important role in the metastasis from primary GC to lymph nodes. However, the role and relevant pathways of miR-10a in GC metastasis remain largely unknown. The present study was performed using 41 GC and 20 normal gastric mucosa tissues. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis demonstrated that MAPK8IP1 was significant downregulated in GC tissue. A statistically significant inverse correlation was detected between miR-10a and MAPK8IP1 mRNA expression levels in GC specimens. Luciferase reporter assay and qPCR results suggested that MAPK8IP1 was a direct target of miR-10a in GC cells. Matrigel invasion assay and wound-healing assay results showed that MAPK8IP1 overexpression rescued the increased migration ability of miR-10a effectors in MKN45 cells. Furthermore, the underlying mechanism of miR-10a functions in GC was explored. The findings indicated that miR-10a-5p directly targets MAPK8IP1, as a major mechanism for gastric cancer metastasis. The results of the present study suggested that miR-10a may be a potential target for the treatment of GC in the future.

Long non-coding RNA XIST promotes cell growth by regulating miR-139-5p/PDK1/AKT axis in hepatocellular carcinoma.

Abnormal expression of long non-coding RNA often contributes to unrestricted growth of cancer cells. Long non-coding RNA XIST expression is upregulated in several cancers; however, its modulatory mechanisms have not been reported in hepatocellular carcinoma. In this study, we found that XIST expression was significantly increased in hepatocellular carcinoma tissues and cell lines. XIST promoted cell cycle progression from the G1 phase to the S phase and protected cells from apoptosis, which contributed to hepatocellular carcinoma cell growth. In addition, we revealed that there was reciprocal repression between XIST and miR-139-5p. PDK1 was identified as a direct target of miR-139-5p. We proposed that XIST was responsible for hepatocellular carcinoma cell proliferation, and XIST exerted its function through the miR-139-5p/PDK1 axis.

Prognostic nutritional index predicts prognosis in patients with metastatic nasopharyngeal carcinoma.

OBJECTIVE: This study aimed to investigate the prognostic value of Onodera's prognostic nutritional index (PNI) in patients with metastatic nasopharyngeal carcinoma (NPC). METHODS: A total of 187 patients with metastatic NPC treated with cisplatin-based chemotherapy were retrospectively reviewed. The PNI was calculated using the following formula: serum albumin level (gram per liter) +0.005× peripheral lymphocyte count (per cubic millimeter). A receiver operating characteristics curve for overall survival (OS) with the highest Youden index was determined to calculate the best cutoff value of PNI. The relationship between PNI and clinicopathological parameters was compared with the χ2 test. Survival analysis was applied to evaluate the predictive value of PNI. RESULTS: The median PNI in this study was 49.0 (ranging from 32.2 to 78.4). The best cutoff value of PNI for OS was 51.0 according to the receiver operating characteristics analysis. The median OS time was 13.0 months. The multivariate analysis indicated that the complete response (hazard ratio 0.681, 95% confidence interval 0.574-0.902; P=0.013) and PNI (hazard ratio 1.732, 95% confidence interval 1.216-2.892; P=0.005) were independent prognostic factors for OS in patients with metastatic NPC. CONCLUSION: This study revealed that PNI is a simple and effective predictor for overall survival in patients with metastatic NPC.

The long non-coding RNA NEAT1 regulates epithelial to mesenchymal transition and radioresistance in through miR-204/ZEB1 axis in nasopharyngeal carcinoma.

Long non-coding RNAs (lncRNAs) play a critical role in cancer progression, including in nasopharyngeal carcinoma (NPC). However, it is still poorly understood whether lncRNA regulates epithelial to mesenchymal transition (EMT) and radioresistance of NPC cells. We found that lncRNA NEAT1 was significantly upregulated in NPC cell lines and tissues. Knockdown of NEAT1 could sensitize NPC cells to radiation in vitro. Further investigation found that NEAT1 regulated radioresistance by modulating EMT phenotype. Furthermore, we found that there was reciprocal repression between NEAT1 and miR-204. ZEB1 was identified as a downstream target of miR-204 and NEAT1 upregulated ZEB1 expression by negatively regulating miR-204 expression. Taking together, we proposed that NEAT1 regulated EMT phenotype and radioresistance by modulating the miR-204/ZEB1 axis in NPC.

Gold nano-particles (AuNPs) carrying anti-EBV-miR-BART7-3p inhibit growth of EBV-positive nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) infection is a major etiological factor for nasopharyngeal carcinoma (NPC). Several EBV-encoded BART miRNAs have been associated with viral latency, immune escape, cell survival, cell proliferation and apoptosis. Here, we report that EBV-miR-BART7-3p, an EBV-encoded BART miRNA highly expressed in NPC, was correlated with cell-cycle progression in vitro and increased tumor formation in vivo. This viral miRNA stimulated the PTEN/PI3K/Akt pathway and induced c-Myc and c-Jun. Knockdown of PTEN mimicked EBV-miR-BART7-3p-induced tumorigenic phenotype. Based on these results, we conducted a therapeutic experiment by using gold nano-particles (AuNPs) carrying anti-EBV-miR-BART7-3p. Silencing of EBV-miR-BART7-3p reduced tumor growth in animal model. We conclude that EBV-miR-BART7-3p favors carcinogenesis, representing a potential target for miRNA-based therapy.

A complementary strategy for enhancement of nanoparticle intracellular uptake.

PURPOSE: The complementary strategy by combining targeting ligand-mediated selectivity and CPP-mediated transmembrane function could be exploit synergies for enhancing cellular uptake of nanoparticles with negative charge. A heparin-based nanoparticles with negative charge was fabricated by complementary strategy, which was expected to attain efficient uptake and simultaneously exert great anticancer activity. METHODS: We synthesized heparin-based nanoparticles with targeting ligand folate and CPP ligand Tat to deliver paclitaxel (H-F-Tat-P NPs). The NPs were characterized by (1)H NMR, DLS and TEM, respectively. The effect of dual ligands on system behavior in aqueous solution was investigated. Moreover, its cellular internalization and anticancer activity were detected by flow cytometry, confocal microscopy and MTT. RESULTS: Folate played a key role in the formation of heparin-based NPs dependent on the balance of amphiphilic Tat and hydrophobic folate. Although H-F-Tat-P NPs primarily entered FR specific and non-specific cells by similar routes, there were no comparability due to cell-type specific variation. Unlike non-specific cells, the complementary ligands could help negative-charged NPs to enhance cellular uptake facilitating its endosome escape in specific cells thereby exhibiting great anticancer activity. CONCLUSIONS: The complementary strategy for negative-charged NPs was presented a promising delivery system for diverse anticancer agents enable simultaneously targeting and drug delivery.

EBV-miR-BART1 is involved in regulating metabolism-associated genes in nasopharyngeal carcinoma.

EBV-miR-BART1 has been found to be highly expressed in some cancers including nasopharyngeal carcinoma (NPC), but its exact roles in the pathogenesis of NPC remain unclear. Here, we did RNA deep sequencing to compare the gene expression profile between EBV-miR-BART1-expressing CNE1 cells and the control cells to determine the possible effects of EBV-miR-BART1 in NPC. Gene expression profiling analysis unexpectedly showed a significant number of up- and down-modulated metabolism-associated genes, such as G6PD, SAT1, ASS1, PAST1, FUT1, SGPL1, DHRS3, B4GALT1, PHGDH, IDH2, PISD, UGT8, LDHB and GALNT1, in EBV-miR-BART1-expressing NPC cells, which were next confirmed by RT-qPCR. Moreover, of these metabolism-genes, PSAT1 and PHGDH expression levels were significantly upregulated and most of other genes were obviously up-expressed in NPC specimens compared with chronic nasopharyngitis (CNP) tissues. Collectively, we for the first time found the effects of EBV-miR-BART1 on the expression of mechanism-associated genes in NPC, suggesting a novel role of EBV-miR-BART1 in cancer metabolism, which remains to be fully elucidated.