HMGB1 promotes tumor progression and invasion through HMGB1/TNFR1/NF-kappaB axis in castration-resistant prostate cancer

xlomafota13 shared this article with you from Inoreader HMGB1 promotes tumor progression and invasion through HMGB1/TNFR1/NF-kappaB axis in castration-resistant prostate cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):2215-2227. eCollection 2021. ABSTRACT Prostate cancer (PCa) is the most common male cancer. Most patients treated with androgen deprivation therapy progress to castration-resistant PCa. To overcome the limitations of this treatment, there is an urgent need to identify more effective treatment targets. High mobility group box 1 protein (HMGB1) is known to be associated with progression, metastasis, and poor prognosis of several solid tumors; however, its role in PCa remains unclear. Thus, we aimed to evaluate the clinical significance and biological roles and mechanism of HMGB1 in PCa. We showed that increased expression of HMGB1 correlated with increased risk of aggressive PCa, and high expression of HMGB1 was associated with poor biochemical recurrence-free survival in a Korean cohort. Additionally, the inhibition of HMGB1 expression significantly reduced cell proliferation, invasive capacity, and NF -κB signaling in vitro. Our results indicated that HMGB1 is a critical factor in the development and progression of PCa. Moreover, we found that HMGB1 directly interacts with TNFR1, and TNFR1 overexpression in HMGB1 knockdown cells reversed the effects of HMGB1 knockdown. Importantly, our results suggest that HMGB1 binding to TNFR1 promotes tumor progression by activating the NF-κB signaling pathway in PCa; therefore, the HMGB1/TNFR1/NF-κB signaling pathway could serve as a novel therapeutic target for improving PCa therapy. PMID:34094679 | PMC:PMC8167672 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

BRCA1-associated protein 1 serves as a tumor suppressor in hepatocellular carcinoma by deubiquitinating and stabilizing PTEN

xlomafota13 shared this article with you from Inoreader BRCA1-associated protein 1 serves as a tumor suppressor in hepatocellular carcinoma by deubiquitinating and stabilizing PTEN Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):2044-2061. eCollection 2021. ABSTRACT BRCA1-associated protein 1 (BAP1) or its mutants have been known to play critical regulatory roles in tumor biology, yet their role in hepatocellular carcinoma (HCC) remains largely unclear. In this study, we detected the mutations of all the exons of BAP1 in 105 HCC patients using Sanger sequencing, and found eight somatic mutations in 6 (5.71%) patients. We also found that the mRNA and protein levels of BAP1 were markedly downregulated in HCC versus the adjacent non-tumor tissues. Wild-type BAP1 but not mutant BAP1 significantly inhibited HCC cell proliferation, invasion, epithelial-mesenchymal transition (EMT) in vitro, and tumor progression and metastasis in vivo. Mechanistically, BAP1 complexed with PTEN and stabilized PTEN via deubiquitination and, furthermore, negatively regulated HCC cell EMT by deactivating the AKT/GSK-3β/Snail pathway. How ever, those tumor-inhibitory effects of BAP1 were abolished by inactivating mutations. Clinically, low BAP1 expression was positively correlated to aggressive tumor phenotypes, which also independently associated with poorer recurrence-free survival and overall survival after curative hepatectomy. Conclusively, our results indicate that BAP1, significantly downregulated, somatically mutated and negatively regulating EMT in HCC, serves as a tumor suppressor of HCC by deubiquitinating and stabilizing PTEN. PMID:34094668 | PMC:PMC8167693 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

High concordance of mutation patterns in 10 common mutated genes between tumor tissue and cell-free DNA in metastatic colorectal cancer

xlomafota13 shared this article with you from Inoreader High concordance of mutation patterns in 10 common mutated genes between tumor tissue and cell-free DNA in metastatic colorectal cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):2228-2237. eCollection 2021. ABSTRACT The concordance of mutation patterns between cell-free DNA (cfDNA) and tumor DNA varies in colorectal cancers (CRCs). Next-generation sequencing (NGS) by targeted sequencing can detect novel genes. We aimed to use NGS to test the concordance between cfDNA and tumor DNA in metastatic CRCs. A total of 95 paired tumor and peripheral blood samples from metastatic CRC patients were included. The tumor DNA and cfDNA were analyzed with a 10-gene NGS panel (Illumina HiSeq2500 system). The median number of mutations in tumor samples was 3 (range 0-7). The most commonly mutated gene was TP53 (63.2%), followed by APC (49.5%), KRAS (35.8%) and FAT4 (15.8%). The concordance of mutation patterns in these 10 genes was as high as 91% between cfDNA and tumor samples in these metastatic CRC patients. A sensitivity of 88.2% and specificity of 100% was fou nd when using KRAS mutation status of cfDNA to predict KRAS mutation in tumor tissue. For tumor DNA with TP53, KRAS, or APC mutations, right-sided CRCs were more likely to develop peritoneal metastases, while for tumor DNA with TP53 mutations, left-sided tumors were more likely to have lung metastases. For cfDNA with TP53 or KRAS mutations, right-sided CRCs were more likely to have peritoneal metastases. Due to the high concordance of mutation patterns between cfDNA and tumor samples, monitoring the mutation pattern of cfDNA may be applicable in the treatment of metastatic CRC. PMID:34094680 | PMC:PMC8167700 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Laryngeal squamous cell carcinoma cell lines show high tolerance for siRNA-mediated CDK1 knockdown

xlomafota13 shared this article with you from Inoreader Laryngeal squamous cell carcinoma cell lines show high tolerance for siRNA-mediated CDK1 knockdown Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):2081-2094. eCollection 2021. ABSTRACT Alterations of the cell cycle checkpoints lead to uncontrolled cell growth and result in tumorigenesis. One of the genes essential for cell proliferation and cell cycle regulation is CDK1. This makes it a potential target in cancer therapy. In our previous study we have shown upregulation of this gene in laryngeal squamous cell carcinoma (LSCC). Here we analyze the impact of siRNA-mediated CDK1 knockdown on cell proliferation and viability, measured with cell growth monitoring and colorimetric test (CCK8 assay), respectively. We proved that a reduction of CDK1 expression by more than 50% has no effect on these cellular processes in LSCC cell lines (n=2). Moreover, using microarrays, we analyzed global gene expression deregulation in these cell lines after CDK1 knockdown. We searched for enriched ontologies in the group of identified 137 differentially expressed genes (>2-fold change). Within this group we found 3 enriched pathways: protein binding (GO:0005515), mitotic nuclear division (GO:0007067) and transmembrane receptor protein tyrosine kinase signaling pathway (GO:0007169) and a group of 11 genes encoding proteins for which interaction with CDK1 was indicated with the use of bioinformatic tools. Among these genes we propose three: CDK6, CALD1 and FYN as potentially dependent on CDK1. PMID:34094670 | PMC:PMC8167681 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

YY1-mediated reticulocalbin-2 upregulation promotes the hepatocellular carcinoma progression via activating MYC signaling

xlomafota13 shared this article with you from Inoreader YY1-mediated reticulocalbin-2 upregulation promotes the hepatocellular carcinoma progression via activating MYC signaling Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):2238-2251. eCollection 2021. ABSTRACT Hepatocellular carcinoma (HCC) is a common digestive tumor with high fatality worldwide. Previous studies have shown that Reticulocalbin-2 (RCN2) was a crucial factor for HCC proliferation, but invasion and migration mechanism of RCN2 contributing to HCC is poorly investigated. In this study, we estimated the RCN2 expression in both patient tissues and cell lines by polymerase chain reaction (PCR) and western blotting (WB), as well as the clinical information of HCC patients from public databases. Biological function induced by RCN2 in vitro and vivo was also researched through multiple functional experiments. Upstream and downstream signal of RCN2 was identified by bioinformatics. We found that up-regulated RCN2 was related to poorer prognosis in HCC patients and attached significance to HCC proliferation, invasion and migration. Luciferase reporter assay and chromatin immunoprecipitation validated that YY1 as the upstream transcription factor of RCN2, facilitating the expression of RCN2. Gene set enrichment analysis indicated that HCC progression induced by RCN2 might be related to MYC signaling. Furthermore, we demonstrated RCN2 reduced proteasomal degradation of MYC and lead to HCC progression. The effects of overexpressed RCN2 in HCC were attenuated by MYC silencing. In conclusion, our study highlighted the vital role of RCN2 in tumor progression and the potential benefit for the treatment of HCC. PMID:34094681 | PMC:PMC8167676 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

GOLPH3 promotes glioma progression by enhancing PHB2-mediated autophagy

xlomafota13 shared this article with you from Inoreader GOLPH3 promotes glioma progression by enhancing PHB2-mediated autophagy Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):2106-2123. eCollection 2021. ABSTRACT Due to the hypoxia and nutrient deficiency microenvironment, malignant glioma exhibits high autophagy activity and autophagy plays a significant role in the occurrence and development of glioma. However, the potential molecular mechanism of autophagy in glioma remains unknown. In this study, we demonstrated that Golgi phosphorylation protein 3 (GOLPH3), a highly conserved protein basically concentrates in the trans-Golgi network, promoted glioma autophagy. Inhibiting autophagy by using chloroquine suppressed the stimulating effect of GOLPH3 on glioma malignant development both in vitro and in vivo. Mechanistically, GOLPH3 interacted with and recruited prohibitin-2 (PHB2), an autophagy receptor of mitochondrion, and LC3-II. PHB2 promoted cell autophagy and down-regulation of PHB2 abolished the effect of GOLPH3 on autophagy. On the side, the relative m RNA and protein levels of GOLPH3 and PHB2 were positively associated with each other and both also correlated with autophagy in glioma tissues. Together, our results revealed that GOLPH3 promotes glioma progression by enhancing PHB2-mediated autophagy and inhibiting autophagy may benefit glioma patients with GOLPH3 high level. The novel GOLPH3-PHB2-autophagy axis maybe a potential and prospective therapeutic target for gliomas. PMID:34094672 | PMC: PMC8167689 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Addition of bromelain and acetylcysteine to gemcitabine potentiates tumor inhibition in vivo in human colon cancer cell line LS174T

xlomafota13 shared this article with you from Inoreader Addition of bromelain and acetylcysteine to gemcitabine potentiates tumor inhibition in vivo in human colon cancer cell line LS174T Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):2252-2263. eCollection 2021. ABSTRACT The combinations of Bromelain and Acetylcysteine (BromAc®) with cytotoxics such as Gemcitabine, 5-Fluorouracil or Oxaliplatin have shown a dramatic reduction in IC50 values in a variety of cancers, including colon cancer, suggesting the possibility of effective treatment without undesired side effects. In the current study, we investigated whether a similar effect is present in vivo using the colorectal cell line LS174T. Animals after acclimatization were randomized and allocated equally in the groups for the different studies (safety, dose-escalation, and efficacy). Drugs were delivered by the intraperitoneal route and animals were monitored for wellbeing. Separately, an efficacy study was conducted with intraperitoneal drug delivery after intraperitoneal tumor induction. At the termination of the experiment, tumors and other tissues were colle cted for evaluation. BromAc® was safe when delivered intraperitoneally in a rat model at the concentrations used. Subsequent investigations of these adjuvants in combination with Gemcitabine, Oxaliplatin, and 5-Fluorouracil in mice were also proven to be safe. Preliminary efficacy studies with Oxaliplatin and 5-Fluorouracil on tumor growth (LS174T) were negative. Gemcitabine was assessed with BromAc® showing an almost 71% tumor inhibition compared to controls. This in vivo study indicates that Gemcitabine at 2 mg/kg in combination with BromAc® 3 mg/300 mg/Kg was effective and safe, supporting its potential for future clinical application. PMID:34094682 | PMC:PMC8167695 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

SETDB1 in cancer: overexpression and its therapeutic implications

xlomafota13 shared this article with you from Inoreader SETDB1 in cancer: overexpression and its therapeutic implications Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):1803-1827. eCollection 2021. ABSTRACT SET Domain Bifurcated Histone Lysine Methyltransferase 1 (SETDB1, ESET, KMT1E) is a H3K9 methyltransferase involved in gene silencing. In recent years, SETDB1 has been implicated as an oncogene in various cancers, highlighting a critical need to better understand the mechanisms underlying SETDB1 amplification, overexpression, and activation. In the following review, we first examine the history of SETDB1, starting from its discovery in 1999 and ending with recent findings. We follow with an outline of the structure and subcellular location of SETDB1, as well as potential mechanisms for regulation of its nuclear transport. Subsequently, we introduce SETDB1's various functions, including its roles in promyelocytic leukemia nuclear body (PML-NB) formation, the methylation and activation of Akt, the silencing of the androgen receptor (AR) gene, retroelement silencing, the inhibition of tumor suppressor p53, and its role in promoting intestinal differentiation and survival. The Cancer Cell Line Encyclopedia (CCLE) screened SETDB1 dependency in 796 cancer cell lines, identifying SETDB1 as a common essential gene in 531 of them, demonstrating that SETDB1 expression is critical for the survival of the majority of cancers. Therefore, we provide a detailed review of the oncogenic effects of SETDB1 overexpression in breast cancer, non-small cell lung cancer, prostate cancer, colorectal cancer, acute myeloid leukemia, glioma, melanoma, pancreatic ductal adenocarcinoma, liver cancer, nasopharyngeal carcinoma, gastric carcinoma, and endometrial cancer. Accordingly, we review several methods that have been used to target SETDB1, such as using Mithramycin A, Mithralog EC-8042, 3'-deazaneplanocin A (DZNep), and paclitaxel. Finally, we conclude by highlighting remaining gaps in knowledge and challenges surrounding SETDB1. Ultimately, our review captures the w ide scope of findings on SETDB1's history, function, its implications in cancer, and provides suggestions for future research in the field. PMID:34094655 | PMC:PMC8167684 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Genetic variants of DOCK2, EPHB1 and VAV2 in the natural killer cell-related pathway are associated with non-small cell lung cancer survival

xlomafota13 shared this article with you from Inoreader Genetic variants of DOCK2, EPHB1 and VAV2 in the natural killer cell-related pathway are associated with non-small cell lung cancer survival Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):2264-2277. eCollection 2021. ABSTRACT Although natural killer (NK) cells are a known major player in anti-tumor immunity, the effect of genetic variation in NK-associated genes on survival in patients with non-small cell lung cancer (NSCLC) remains unknown. Here, in 1,185 with NSCLC cases of a discovery dataset, we evaluated associations of 28,219 single nucleotide polymorphisms (SNPs) in 276 NK-associated genes with their survival. These patients were from the reported genome-wide association study (GWAS) from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We further validated the findings in an additional 984 cases from the Harvard Lung Cancer Susceptibility (HLCS) Study. We identified three SNPs (i.e., DOCK2 rs261083 G>C, VAV2 rs2519996 C>T and EPHB1 rs36215 A>G) to be independently associated with overall survival (OS) in NSCLC cases with ad justed hazards ratios (HRs) of 1.16 (95% confidence interval [CI] = 1.07-1.26, P = 3.34×10-4), 1.28 (1.12-1.47, P = 4.57×10-4) and 0.75 (0.67-0.83, P = 1.50×10-7), respectively. Additional joint assessment of the unfavorable genotypes of the three SNPs showed significant associations with OS and disease-specific survival of NSCLC cases in the PLCO dataset (P trend<0.0001 and <0.0001, respectively). Moreover, the survival-associated DOCK2 rs261083 C allele had a significant correlation with reduced DOCK2 transcript levels in lung adenocarcinoma (LUAD), while the rs36215 G allele was significantly correlated with reduced EPHB1 transcript levels in lymphoblastoid cell lines in the 1000 Genomes Project. These results revealed that DOCK2 and EPHB1 genetic variants may be prognostic biomarkers of NSCLC survival, likely via transcription regulation of respective genes. PMID:34094683 | PMC:PMC8167686 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Gene polymorphism-related differences in the outcomes of abiraterone for prostate cancer: a systematic overview

xlomafota13 shared this article with you from Inoreader Gene polymorphism-related differences in the outcomes of abiraterone for prostate cancer: a systematic overview Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):1873-1894. eCollection 2021. ABSTRACT Numerous prostate cancer (PC) associated genes have been reported in previous genome-wide association studies. Elucidation of prostate cancer pharmacogenomics have enhanced studies into the impact of germline genetic changes on treatment, in addition to evaluating related genomic alterations and biomarkers in prostate tumor tissues. Currently, Abiraterone (Abi) is used as one of the therapeutic options for PC. In this article, germline variants that have been associated with responses to Abi in patients with advanced PC are summarized. These include biomarker genes such as CYP17A1, AR-V7, HSD3B1, SLCO2B1, SULT1E1, and SRD5A2 that are involved in homologous recombination, as well as in gene expression mutations in important signaling pathways, such as WNT and Abi metabolic pathways. PMID:34094659 | PMC:PMC8167691 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Epithelial-mesenchymal transition induced by SARS-CoV-2 required transcriptional upregulation of Snail

xlomafota13 shared this article with you from Inoreader Epithelial-mesenchymal transition induced by SARS-CoV-2 required transcriptional upregulation of Snail Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):2278-2290. eCollection 2021. ABSTRACT The engagement of human angiotensin-converting enzyme 2 (hACE2) and SARS-CoV-2 spike protein facilitate virus spread. Thus far, ACE2 and TMPRSS2 expression is correlated with the epithelial-mesenchymal transition (EMT) gene signature in lung cancer. However, the mechanism for SARS-CoV-2-induced EMT has not been thoroughly explored. Here, we showed that SARS-CoV-2 induces EMT phenotypic change and stemness in breast cancer cell model and subsequently identified Snail as a modulator for this regulation. The in-depth analysis identifies the spike protein (S), but not envelope (E), nucleocapsid (N), or membrane protein (M), of SARS-CoV-2 induces EMT marker changes. Suppression of Snail expression in these cells abrogates S protein-induced invasion, migration, stemness, and lung metastasis, suggesting that Snail is required for SARS-CoV-2-mediated aggressive phenotype in cancer. This study reveals an important oncogenic role of SARS-CoV-2 in triggering breast cancer metastasis through Snail upregulation. PMID:34094684 | PMC:PMC8167694 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.