PTEN inhibition enhances sensitivity of ovarian cancer cells to the poly (ADP-ribose) polymerase inhibitor by suppressing the MRE11-RAD50-NBN complex.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPis) can effectively treat ovarian cancer patients with defective homologous recombination (HR). Loss or dysfunction of PTEN, a typical tumour suppressor, impairs double-strand break (DSB) repair. Hence, we explored the possibility of inhibiting PTEN to induce HR deficiency (HRD) for PARPi application. METHODS: Functional studies using PTEN inhibitor VO-OHpic and PARPi olaparib were performed to explore the molecular mechanisms in vitro and in vivo. RESULTS: In this study, the combination of VO-OHpic with olaparib exhibited synergistic inhibitory effects on ovarian cancer cells was demonstrated. Furthermore, VO-OHpic was shown to enhance DSBs by reducing nuclear expression of PTEN and inhibiting HR repair through the modulation of MRE11-RAD50-NBN (MRN) complex, critical for DSB repair. TCGA and GTEx analysis revealed a strong correlation between PTEN and MRN in ovarian cancer. Mechanistic studies indicated that VO-OHpic reduced expression of MRN, likely by decreasing PTEN/E2F1-mediated transcription. Moreover, PTEN-knockdown inhibited expression of MRN, increased sensitivities to olaparib, and induced DSBs. In vivo experiments showed that the combination of VO-OHpic with olaparib exhibited enhanced inhibitory effects on tumour growth. CONCLUSIONS: Collectively, this study highlights the potential of PTEN inhibitors in combination therapy with PARPis to create HRD for HRD-negative ovarian cancers.

Impact of open and minimally invasive surgery on postoperative wound complications in patients undergoing prostate surgery: A meta-analysis.

In this article, we analysed the therapeutic efficacy of open radical prostatectomy (ORP) and minimally invasive surgery (MIS) after operation for the treatment of post-operation complications. In summary, because of the broad methodology of the available trials and the low number of trials, the data were limited. The investigators combined the results of six of the 211 original studies. We looked up 4 databases: PubMed, EMBASE, Web of Science and the Cochrane Library. A total of six publications were selected. The main result was the rate of post-operation wound complications. Secondary results were the time of operation and the duration of hospitalization. Our findings indicate that the minimal invasive operation can decrease the incidence of wound infections (OR, 0.61; 95% CI: 0.42,0.90, p = 0.01), bleeding (MD, -293.09; 95% CI: -431.48, -154.71, p < 0.0001), and length of stay in the hospital compared with open surgery (MD, -1.85; 95% CI: -3.52, -0.17, p = 0.03), but minimally invasive surgery increased patient operative time (MD, 51.45; 95% CI: 40.99, 61.92, p < 0.0001). Compared with the open operation, the microinvasive operation has the superiority in the treatment of the wound complications following the operation of radical prostatic carcinoma. But the operation time of the microinvasive operation is much longer. Furthermore, there is a certain amount of bias among the various studies, so it is important to be cautious in interpretation of the findings.

Cognitive impairment is associated with BDNF-TrkB signaling mediating synaptic damage and reduction of amino acid neurotransmitters in heart failure.

Heart failure (HF) is often accompanied by cognitive impairment (CI). Brain-derived neurotrophic factor (BDNF) deficiency is closely associated with CI. However, the role and mechanism of BDNF in HF with CI is still not fully understood. Here, the case-control study was designed including 25 HF without CI patients (HF-NCI) and 50 HF with CI patients (HF-CI) to investigate the predictive value of BDNF in HF-CI while animal and cell experiments were used for mechanism research. Results found that BDNF levels in serum neuronal-derived exosomes were downregulated in HF-CI patients. There was no significant difference in serum BDNF levels among the two groups. HF rats showed obvious impairment in learning and memory; also, they had reduced thickness and length of postsynaptic density (PSD) and increased synaptic cleft width. Expression of BDNF, TrkB, PSD95, and VGLUT1 was significantly decreased in HF rats brain. In addition, compared with sham rats, amino acids were significantly reduced with no changes in the acetylcholine and monoamine neurotransmitters. Further examination showed that the number of synaptic bifurcations and the expression of BDNF, TrkB, PSD95, and VGLUT1 were all decreased in the neurons that interfered with BDNF-siRNA compared with those in the negative control neurons. Together, our results demonstrated that neuronal-derived exosomal BDNF act as effective biomarkers for prediction of HF-CI. The decrease of BDNF in the brain triggers synaptic structural damage and a decline in amino acid neurotransmitters via the BDNF-TrkB-PSD95/VGLUT1 pathway. This discovery unveils a novel pathological mechanism underlying cognitive impairment following heart failure.

Therapeutic targeting of DNA damage repair pathways guided by homologous recombination deficiency scoring in ovarian cancers.

The susceptibility of cells to DNA damage and their DNA repair ability are crucial for cancer therapy. Homologous recombination is one of the major repairing mechanisms for DNA double-strand breaks. Approximately half of ovarian cancer (OvCa) cells harbor homologous recombination deficiency (HRD). Considering that HRD is a major hallmark of OvCas, scholars proposed HRD scoring to evaluate the HRD degree and guide the choice of therapeutic strategies for OvCas. In the last decade, synthetic lethal strategy by targeting poly (ADP-ribose) polymerase (PARP) in HR-deficient OvCas has attracted considerable attention in view of its favorable clinical effort. We therefore suggested that the uses of other DNA damage/repair-targeted drugs in HR-deficient OvCas might also offer better clinical outcome. Here, we reviewed the current small molecule compounds that targeted DNA damage/repair pathways and discussed the HRD scoring system to guide their clinical uses.

RAD54B mutations enhance the sensitivity of ovarian cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors.

Synthetic lethal targeting of homologous recombination (HR)-deficient ovarian cancers (OvCas) with poly(ADP-ribose) polymerase inhibitors (PARPis) has attracted considerable attention. Olaparib was the first PARPi approved by the Food and Drug Administration, offering significant clinical benefits in BRCA1/2-deficient OvCas. However, only approximately 20% of OvCa patients harbor BRCA1/2 mutations. Given the shared roles that BRCA1/2 have with other HR regulators, alterations in HR genes may also contribute to "BRCAness profiles" in OvCas. RAD54B has been considered a key player in HR repair, although its roles and therapeutic potential in cancers need further investigation. Here, we identified 22 frequently mutated HR genes by whole-exome sequencing of OvCa tissues from 82 patients. To our surprise, 7.3% of patients were found to harbor mutations of RAD54B, the third-highest mutated gene among patients. We determined that RAD54B-mutated tumor tissues harbored more DNA double-strand breaks than normal tissues. Additionally, we found that RAD54B knockdown inhibited HR repair, enhanced sensitivities of OvCa cells with increased DNA double-strand breaks to olaparib, and induced apoptosis. Enhanced inhibitory effects of olaparib on the growth of ES2 xenograft tumors were further demonstrated by RAD54B knockdown. Finally, we show that restoration with wildtype RAD54B rather than RAD54BN593S and RAD54BH219Y, identified in patients, abolished the effects of RAD54B knockdown, indicating these RAD54B mutants probably malfunctioned in HR repair. Our investigations may offer insight into the contributions of RAD54B mutations to synthetic lethality with olaparib treatment in OvCas, enrich the gene list for "HR deficiency scoring," and expand the applications of PARPis.

HSP90 Inhibitor Ganetespib Enhances the Sensitivity of Mantle Cell Lymphoma to Bruton's Tyrosine Kinase Inhibitor Ibrutinib.

Mantle cell lymphoma (MCL) is a highly aggressive and heterogeneous B-cell lymphoma. Though Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has shown great efficacy as a single agent for MCL treatment, the real-world use of ibrutinib is still subject to limitations. Our previous study has shown the treatment with HSP90 inhibitor ganetespib can attack major targets of MCL, luckily complementary to ibrutinib's targets. In this study, transient ganetespib treatment sensitizes MCL cells to ibrutinib as manifested by the significant decrease of IC50 values, percentages of EdU (5-Ethynyl-2'-deoxyuridine) positive cells, and levels of p-AKT and NF-κB after combinational treatment. Additionally, pretreatment with ganetespib enhanced cell cycle arrest induced by ibrutinib at G0/G1 phase and significantly decreased levels of cell cycle promoting proteins CDK2, 4, and 6. Pretreatment with ganetespib also enhanced cell apoptosis induced by ibrutinib through the upregulation of cleaved-caspase 9 and downregulation of BCL-2 in MCL cells at the molecular level. The sequential administration of ganetespib and ibrutinib had similar effects on increasing DNA damage as the transient treatment with ganetespib as demonstrated by the improved percentage of γH2AX and 53BP1 foci. Furthermore, ganetespib significantly increased inhibition of tumor growth mediated by ibrutinib in vivo, confirmed by the changes of the expression levels of Ki-67 and BCL-2 through immunohistochemistry assays. This study indicates that HSP90 inhibitor ganetespib maybe ideal for the combinational use with BTK inhibitor ibrutinib to target major pathogenesis-associated signaling pathways for MCL treatment which may help identify new possibilities for clinical trials.

Sp1 is overexpressed and associated with progression and poor prognosis in bladder urothelial carcinoma patients.

BACKGROUND: Specificity protein 1 (Sp1) is a transcription factor that exerts key functions in the carcinogenesis and progression of various types of cancer. However, its expression and prognostic value in bladder urothelial carcinoma (BUC) have yet to be completely elucidated. METHODS: The present study performed reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to examine Sp1 mRNA expression in 12 pairs of urothelial carcinoma and adjacent normal bladder tissues. Immunohistochemistry (IHC) was performed in 113 paraffin-embedded urothelial carcinoma tissues to detect the expression of Sp1. Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the correlation between Sp1 expression and patient prognosis. RESULTS: The mRNA expression of Sp1 was elevated in the urothelial carcinoma by RT-qPCR compared with their paired normal bladder tissues. Among 113 cases of patients with urothelial carcinoma, there were 39 low histological grade and 74 high histological grade, 61 unifocal tumor and 52 multifocal tumor, 78 cases in Ta, T1, and T2 stages, and 35 cases in T3 and T4 stages. The enhanced expression of Sp1 mRNA was observed in tumors with a high histological grade, and invasive and metastatic samples. Immunohistochemistry revealed that Sp1 high expression was significantly correlated with the histological grade, tumor stage, vascular invasion, lymph node metastasis and distant metastasis (P < 0.05). Kaplan-Meier analysis demonstrated that elevated Sp1 expression in cancer tissue was correlated with a significantly poor overall survival (OS) and disease-free survival (DFS) compared with samples with low Sp1 expression (P < 0.05). Multivariate analyses by Cox's proportional hazard model also revealed that the expression of Sp1 was an independent prognostic factor in urothelial carcinoma. CONCLUSION: Sp1 expression is significantly elevated in urothelial carcinoma and may be used to identify a subset of patients with aggressive behaviors and poor clinical outcomes. Sp1 is a potential novel independent prognostic biomarker for patients with urothelial carcinoma following surgery.

Partitioning defective 6 homolog alpha (PARD6A) promotes epithelial-mesenchymal transition via integrin ß1-ILK-SNAIL1 pathway in ovarian cancer.

Partitioning-defective protein 6 (Par6) family proteins have been demonstrated to be closely associated with the occurrence and development of cancers. It is well accepted that dysregulation of epithelial-mesenchymal transition (EMT) greatly contributes to carcinogenesis and metastases of ovarian cancer. So far, the roles of Par6 in EMT of ovarian cancer are not clear. Functional experiments were carried out to study the roles of PARD6A in EMT of ovarian cancer in vitro and in vivo, and EMT pathways potentially affected by PARD6A expression were screened. We found that PARD6A was significantly highly expressed in tissues of ovarian cancer patients in III-IV stages, poorly differentiated or with lymphatic metastases versus I-II stages, moderately or well differentiated, or without lymphatic metastases, respectively. PARD6A knockdown suppressed EMT of SKOV3 and A2780 cells in vitro and ovarian cancer metastasis in vivo, while overexpression of PARD6A promoted EMT in HO8910 and OVCAR8 cells. It was indicated that PARD6A affected EMT of ovarian cancer cells through SNAIL1 signaling pathway and subsequently modulated the expression of VIMENTIN and E-cadherin, which was further confirmed by knockdown and overexpression of SNAIL1 experiments. PARD6A was also demonstrated to regulate expression of SNAIL1 by modulating integrin ß1 and ILK proteins, specifically it was shown that the transcription of SNAIL1 was regulated by ILK in this study. In addition, expression of ILK in ovarian cancer tissues was demonstrated to be correlated with tumor stages and lymphatic metastases clinically. In this study, we identified a novel role of PARD6A as an inducer of cell migration and invasion, which is likely to play an important role in metastasis of ovarian cancer. The molecular pathways of EMT mediated by PARD6A-Integrin ß1-ILK-SNAIL1 and finally implemented by E-cadherin and VIMENTIN may provide a novel strategy for drug development for ovarian cancer therapy in the near future.

Systematic review and meta-analysis on laparoscopic cystectomy in bladder cancer.

BACKGROUND: This study aimed to systematically evaluate the efficacy of laparoscopic radical cystectomy (LRC) surgical therapy in patients with bladder cancer (BC), and to provide evidence for the clinical treatment of BC. METHODS: The Embase, Ovid, PubMed, Medline, Springer, and Web of Sciences database were searched to screen articles with clinical controlled trials on LRC treatment of BC. The Cochrane Handbook 5.0.2 software and Review Manager 5.3 software were adopted to evaluate the risk of bias and to perform a meta-analysis of the included articles in this study. RESULTS: A total of 12 articles were obtained, including 1,283 research cases. The meta-analysis results showed that relative to the control group (Ctrl), the observation group (Observ group) had significantly lower intraoperative blood loss (IBL) after LRC [mean difference (MD) =-458.75; 95% confidential interval (CI): -505.75 to -411.76; Z=19.13; P<0.00001], blood transfusion rate (BTR) (odds ratio =0.36; 95% CI: 0.13-0.94; Z=2.08; and P=0.04), use of analgesics (MD =-24.53; 95% CI: -39.04 to -10.01; Z=3.31; and P=0.0009), and incidence of postoperative complications (Risk ratio =0.58; 95% CI: 0.39-0.85; Z=2.77; and P=0.006). However, and the length of hospital stay could not be shortened (MD =-2.43; 95% CI: -4.83 to -0.02; Z=1.98; and P=0.05). DISCUSSION: LRC treatment of BC could effectively reduce the amount of IBS, and lower the intraoperative BTR, use of analgesics, and incidence of postoperative complications. Therefore, it could be used in the clinical surgical treatment of BC patients.

Mesenchymal Stem Cell Exosomes in the Treatment of Myocardial Infarction: a Systematic Review of Preclinical In Vivo Studies.

Several prior studies have highlighted the promise of mesenchymal stem cells (MSCs) as tools for treating myocardial infarction (MI) patients. While MSCs were initially thought to mediate post-MI repair through differentiation and replacement of injured cells, they are now thought to function by releasing exosomes carrying important cargos which can prevent apoptosis and facilitate revascularization in the context of MI. Herein, we comprehensively survey prior preclinical studies examining MSC-derived exosomes (MSC-Exos) utility for the repair of MI-related tissue injury. In total, 24 relevant studies were identified in the PubMed, Web of Science, Embase, and Cochrane Library databases as per the PRISMA guidelines. In most studies, exosome-treated rodents exhibited improved cardiac function and angiogenesis together with decreased apoptotic cell death. MSC-Exos thus offer beneficial therapeutic efficacy when treating MI injury. However, further work will be necessary to standardize experimental preclinical models and to validate these results. This systematic review provides a comprehensive overview of previous preclinical studies on the utility of exosomes derived from mesenchymal stem cells (MSCs) in the repair of myocardial infarction (MI) injury.

Sirolimus or Everolimus Improves Survival After Liver Transplantation for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

The effects of mammalian target of rapamycin (mTOR) inhibitors (sirolimus [SRL] and everolimus [EVL]) on survival in liver transplantation (LT) recipients with hepatocellular carcinoma (HCC) remain the subject of intense research. Therefore, we performed this systematic review and meta-analysis to investigate the potential survival benefits of mTOR inhibitors (mTORis). Embase, PubMed, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for all randomized controlled trials (RCTs) and cohort studies investigating effects of SRL or EVL on LT recipients for HCC. The primary outcomes were 1-, 2-, 3-, and 5-year overall survival (OS), and the secondary outcomes were 1-, 2-, and 3-year recurrence-free survival (RFS) and adverse effects. Pooled relative risks (RRs) with 95% confidence interval (CI) were calculated by a fixed or random effects model with Mantel-Haenszel weighting. Subgroup analyses were performed according to crucial clinical characteristics. We also conducted sensitivity analyses to assess the reliability of our findings. A total of 17 studies were included. OS was improved in both RCTs (1 year: RR, 1.04; 95% CI, 1.00-1.08; 2 years: RR, 1.09; 95% CI, 1.02-1.16; 3 years: RR, 1.13; 95% CI, 1.04-1.24; 5 years: RR, 1.13; 95% CI, 1.02-1.26) and cohort studies (1 year: RR, 1.13; 95% CI, 1.06-1.20; 2 years: RR, 1.24; 95% CI, 1.16-1.32; 3 years: RR, 1.24; 95% CI, 1.15-1.34; 5 years: RR, 1.17; 95% CI, 1.10-1.24), with a lower risk of renal toxicity (RR, 0.75; 95% CI, 0.60 to 0.93). The 1-, 2-, and 3-year RFS were also improved. Current evidence indicates that SRL- or EVL-based immunosuppression improves OS and RFS with a lower risk of renal toxicity compared with mTORi-free immunosuppression. Nevertheless, results must be interpreted with caution.

Progression of Prothrombin Induced by Vitamin K Absence-II in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related death worldwide. Due to the lack of efficient tools for early detection, asymptomatic HCC patients are diagnosed at an advanced stage, leading to a poor prognosis. To improve survival, serum biomarker prothrombin induced by vitamin K absence-II (PIVKA-II) was under investigation. PIVKA-II is an abnormal protein produced in HCC. The coagulation function was insufficient due to the lack of Gla residues. Elevated PIVKA-II was associated with bad tumor behavior in terms of proliferation, metastasis, and invasion. Three major signaling pathways were proposed to clarify the mechanism. With the advantages including affordability, minimal invasiveness, convenience, and efficiency, PIVKA-II could improve HCC management consisting of four aspects. First, PIVKA-II was an effective and dynamic tool for improving HCC surveillance in high-risk population. Changes in the serum levels of PIVKA-II provided valuable molecular alteration information before imaging discovery. Second, PIVKA-II offered a complementary approach for HCC early detection. Compared to traditional diagnostic approaches, the combination of PIVKA-II and other biomarkers had better performance. Third, PIVKA-II was an indicator for the assessment of response to treatment in HCC. Preoperative assessment was for selecting personalized therapy, and postoperative measurement was for assessing treatment efficacy. Fourth, PIVKA-II was considered as a prognostic predictor for HCC. Patients with elevated PIVKA-II were more likely to develop microvascular invasion, metastasis, and recurrence.

Effect of vascular resection for perihilar cholangiocarcinoma: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of vascular resection (VR), including portal vein resection (PVR) and hepatic artery resection (HAR), on short- and long-term outcomes in patients with perihilar cholangiocarcinoma (PHC). BACKGROUND: Resection surgery and transplantation are the main treatment methods for PHC that provide a chance of long-term survival. However, the efficacy and safety of VR, including PVR and HAR, for treating PHC remain controversial. METHODS: This study was registered at the International Prospective Register of Systematic Reviews (CRD42020223330). The EMBASE, PubMed, and Cochrane Library databases were used to search for eligible studies published through November 28, 2020. Studies comparing short- and long-term outcomes between patients who underwent hepatectomy with or without PVR and/or HAR were included. Random- and fixed-effects models were applied to assess the outcomes, including morbidity, mortality, and R0 resection rate, as well as the impact of PVR and HAR on long-term survival. RESULTS: Twenty-two studies including 4,091 patients were deemed eligible and included in this study. The meta-analysis showed that PVR did not increase the postoperative morbidity rate (odds ratio (OR): 1.03, 95% confidenceinterval (CI): [0.74-1.42], P = 0.88) and slightly increased the postoperative mortality rate (OR: 1.61, 95% CI [1.02-2.54], P = 0.04). HAR did not increase the postoperative morbidity rate (OR: 1.32, 95% CI [0.83-2.11], P = 0.24) and significantly increased the postoperative mortality rate (OR: 4.20, 95% CI [1.88-9.39], P = 0.0005). Neither PVR nor HAR improved the R0 resection rate (OR: 0.70, 95% CI [0.47-1.03], P = 0.07; OR: 0.77, 95% CI [0.37-1.61], P = 0.49, respectively) or long-term survival (OR: 0.52, 95% CI [0.35-0.76], P = 0.0008; OR: 0.43, 95% CI [0.32-0.57], P < 0.00001, respectively). CONCLUSIONS: PVR is relatively safe and might benefit certain patients with advanced PHC in terms of long-term survival, but it is not routinely recommended. HAR results in a higher mortality rate and lower overall survival rate, with no proven benefit.

HSP90 inhibition downregulates DNA replication and repair genes via E2F1 repression.

Mantle cell lymphoma (MCL) is an especially aggressive and highly heterogeneous mature B-cell lymphoma. Heat shock protein 90 (HSP90) is considered an attractive therapeutic target in a variety of cancers, including MCL, but no HSP90 inhibitors have succeeded in the clinical trials to date. Exploring fine mechanisms of HSP90 inhibition in cancer cells may shed light on novel therapeutic strategies. Here, we found that HSP90 knockdown and continuous inhibition with ganetespib inhibited growth of MCL cells in vitro and in vivo. To our surprise, transient exposure over 12 h was almost as efficient as continuous exposure, and treatment with ganetespib for 12 h efficiently inhibited growth and induced G1 cell cycle arrest and apoptosis of MCL cells. Transcriptome analysis complemented by functional studies was performed to define critical MCL signaling pathways that are exceptionally sensitive to HSP90 inhibition and vital to cell fate. Six genes (cell division cycle 6, cell division cycle 45, minichromosome maintenance 4, minichromosome maintenance 7, RecQ-mediated genome instability 2, and DNA primase polypeptide 1) involved in DNA replication and repair were identified as consistently downregulated in three MCL cell lines after transient ganetespib treatment. E2F1, an important transcription factor essential for cell cycle progression, was identified as a ganetespib target mediating transcriptional downregulation of these six genes, and its stability was also demonstrated to be maintained by HSP90. This study identifies E2F1 as a novel client protein of HSP90 that is very sensitive and worthy of targeting and also finds that HSP90 inhibitors may be useful in combination therapies for MCL.

COPB2: A Novel Prognostic Biomarker That Affects Progression of HCC.

PURPOSE: This study is aimed at investigating the expression, underlying biological function, and clinical significance of coatomer protein complex subunit beta 2 (COPB2) in hepatocellular carcinoma (HCC). METHODS: HCC-related data were extracted from The Cancer Genome Atlas (TCGA) database, International Cancer Genome Consortium (ICGC) database, and Gene Expression Omnibus (GEO) database. A logistic regression module was applied to analyze the relationship between the expression of COPB2 and clinicopathologic characteristics. The Cox proportional hazard regression model and Kaplan-Meier method were used for survival analysis. Gene set enrichment analysis (GSEA) was used to annotate the underlying biological functions. Loss-of-function experiments were conducted to determine the underlying mechanisms. RESULTS: COPB2 was overexpressed in HCC, and high expression of COPB2 was significantly correlated with higher alpha fetoprotein (AFP) (odds ratio (OR) = 1.616, >20 vs. ≤20, p < 0.05), stage (OR = 1.744, III vs. I, p < 0.05), and grade (OR = 1.746, G4+G3 vs. G2+G1, p < 0.05). Kaplan-Meier survival analysis showed that HCC patients with high COPB2 expression had a worse prognosis than those with low COPB2 expression (p < 0.0001 for TCGA cohort, p < 0.05 for ICGC cohort). The univariate Cox (hazard ratio (HR) = 1.068, p < 0.0001) and multivariate Cox (HR = 2.011, p < 0.05) regression analyses suggested that COPB2 was an independent risk factor. GSEA showed that mTOR and other tumor-related signaling pathways were differentially enriched in the high COPB2 expression phenotype. Silencing of COPB2 inhibited the proliferation, migration, and invasion abilities by suppressing epithelial-mesenchymal transition and mTOR signaling. CONCLUSION: COPB2 is a novel prognostic biomarker and a promising therapeutic target for HCC.

Analysis of N6-Methyladenosine Modification Patterns and Tumor Immune Microenvironment in Pancreatic Adenocarcinoma.

Background: Pancreatic adenocarcinoma (PAAD) is a rare cancer with a poor prognosis. N6-methyladenosine (m6A) is the most common mRNA modification. However, little is known about the relationship between m6A modification and the tumor immune microenvironment (TIME) in PAAD. Methods: Based on 22 m6A regulators, m6A modification patterns of PAAD samples extracted from public databases were systematically evaluated and correlated with the tumor immune and prognosis characteristics. An integrated model called the "m6Ascore" was constructed, and its prognostic role was evaluated. Results: Three different m6Aclusters and gene clusters were successively identified; these clusters were characterized by differences in prognosis, immune cell infiltration, and pathway signatures. The m6Ascore was constructed to quantify the m6A modifications of individual patients. Subsequent analysis revealed that m6Ascore was an independent prognostic factor of PAAD and could be a potential indicator to predict the response to immunotherapy. Conclusion: This study comprehensively evaluated the features of m6A modification patterns in PAAD. m6A modification patterns play a non-negligible role in the TIME of PAAD. m6Ascore provides a more holistic understanding of m6A modification in PAAD, and will help clinicians predict the prognosis and response to immunotherapy.

Roles of MYC-targeting long non-coding RNA MINCR in cell cycle regulation and apoptosis in non-small cell lung Cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer death in the world, and has a relatively low survival rate. Long non-coding RNAs (lncRNAs) have been demonstrated to modulate cancer progression through a variety of molecular mechanisms. We sought to investigate the role and potential mechanism of MYC-induced long non-coding RNA (MINCR) in NSCLC. METHODS: Expression levels of MINCR was first identified using The Cancer Genome Atlas (TCGA), further confirmed with specimens from 29 NSCLC patients and three cell lines using qRT-PCR. Overexpression and knockdown of MINCR were performed in NSCLC cell lines through MINCR overexpression vectors and synthesized siRNAs, respectively. The roles of MINCR in NSCLC cell lines, such as cell proliferation, cell cycle arrest, and apoptosis, were identified by MTT, flow cytometry, and Western blot. The modulation of MINCR-regulated genes, including c-Myc and its downstream effectors, as well as apoptosis-associated genes, was analyzed using Western blot. RESULTS: MINCR expression was increased in NSCLC patients from TCGA datasets, and was also significantly increased in our collected specimens from NSCLC patients and NSCLC cell lines. Knocking down of MINCR greatly inhibited the growth of NSCLC cell lines PC9 and A549. In addition, silencing of MINCR induced cell cycle arrest and apoptosis. Furthermore, silencing of MINCR reduced the expression levels of oncogene c-Myc and its downstream cyclin A, cyclin D, CD4, and CDK2, as well as apoptosis-associated Bcl-2, while significantly increased the expression levels of cleaved PARP-1. In the meantime, overexpression of MINCR remarkably enhanced cell proliferation of PC9 cells and activated c-Myc and its downstream effectors. CONCLUSION: MINCR exerted inhibitory effects on the cell cycle arrest and apoptosis of NSCLC cells by activating c-Myc and its downstream effectors, suggesting that this lncRNA could be used as a potential therapeutic target for the treatment of NSCLC.

NOD-like receptor signaling in inflammation-associated cancers: From functions to targeted therapies.

BACKGROUND: Recently, many studies have reported that some botanicals and natural products were able to regulate NOD-like receptor signaling. NOD-like receptors (NLRs) have been established as crucial regulators in inflammation-associated tumorigenesis, angiogenesis, cancer cell stemness and chemoresistance. NLRs specifically sense pathogen-associated molecular patterns and respond by activating other signaling regulators, including Rip2 kinase, NF-κB, MAPK and ASC/caspase-1, leading to the secretion of various cytokines. PURPOSE: The aim of this article is to review the molecular mechanisms of NOD-like receptor signaling in inflammation-associated cancers and the NLRs-targeted botanicals and synthetic small molecules in cancer intervention. RESULTS: Aberrant activation of NLRs occurs in various cancers, orchestrating the tissue microenvironment and potentiating neoplastic risk. Blocking NLR inflammasome activation by botanicals or synthetic small molecules may be a valuable way to prevent cancer progression. Moreover, due to the roles of NLRs in regulating cytokine production, NLR signaling may be correlated with senescence-associated secretory phenotype. CONCLUSION: In this review, we discuss how NLR signaling is involved in inflammation-associated cancers, and highlight the NLR-targeted botanicals and synthetic small molecules in cancer intervention.