BCAT1 knockdown-mediated suppression of melanoma cell proliferation and migration is associated with reduced oxidative phosphorylation

xlomafota13 shared this article with you from Inoreader BCAT1 knockdown-mediated suppression of melanoma cell proliferation and migration is associated with reduced oxidative phosphorylation Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):2670-2683. eCollection 2021. ABSTRACT Malignant melanoma has a high mutational rate. As a result, resistance to current therapies is common. Consequently, there is an unmet medical need to develop novel therapies. Recent data suggest that branched-chain amino acid transaminase 1 (BCAT1) is overexpressed in multiple cancers, and such overexpressed BCAT1 is necessary for individual cancer progression. Therefore, BCAT1 appears to be a good target in cancer treatment. Additionally, because its expression in healthy tissues is highly restricted in adults and is limited to the brain, ovary, and placenta, BCAT1 is especially an ideal target in cancer therapies. Currently, the function of BCAT1 in malignant melanoma has not been demonstrated. Therefore, we investigated the role of BCAT1 in the proliferation and migration of malignant melanomas using human samples and mouse malignant B16 melanoma cell line. Ou r data showed that BCAT1 was overexpressed in malignant melanoma tissues both in humans and mice. Besides, BCAT1 knockdown suppressed melanoma cell proliferation and migration, which was associated with reduced oxidative phosphorylation. Collectively, our data indicate that BCAT1 is a promising therapeutic target for the treatment of malignant melanomas. PMID:34249421 | PMC:PMC8263658 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

TAFs contributes the function of PTPN2 in colorectal carcinogenesis through activating JAK/STAT signaling pathway

xlomafota13 shared this article with you from Inoreader TAFs contributes the function of PTPN2 in colorectal carcinogenesis through activating JAK/STAT signaling pathway Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3085-3097. eCollection 2021. ABSTRACT The morbidity and mortality of colorectal cancer (CRC) ranks fourth worldwide, moreover, the tumor microenvironment (TME) of CRC is quite complex, and is one of the necessary factors affecting promotion of tumor metastasis. PTPN2 is a tumor suppressor which plays an important role in cancer-related downstream molecular pathway. FSP-1 is highly-expressed in multiple types of tumor tissues and is a biomarker of stromal fibroblasts. To examine the function of PTPN2 in the metastasis of CRC, the study evaluated the co-expression level of PTPN2 and FSP-1 in CRC tissues by double staining, and demonstrated the relationship with clinical information about each patient. The roles of PTPN2 and FSP-1 were detected in vitro by proliferation and transwell assay through knockdown of expression level of PTPN2. Lower PTPN2 with higher FSP-1 expression was correlated with poor survival outcomes in CRC. TAFs contribute to the migration function of PTPN2 in CRC in vitro through inducing changes in the level of TGF-β1. Western blot and qRT-PCR assays were used to detect the mechanism of PTPN2 regulation of migration with TAFs in the JAK/STAT signaling pathway, moreover, TAFs contributed the function of PTPN2 in colorectal carcinogenesis in vivo. In summary, the study shed light on the effect of TAFs contributes the function of PTPN2 in colorectal carcinogenesis through activating JAK/STAT signaling pathway. In addition, double-staining assay could give us a unique perspective from which to study TME in CRC. PMID:34249446 | PMC:PMC8263690 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Mortalin maintains breast cancer stem cells stemness via activation of Wnt/GSK3beta/beta-catenin signaling pathway

xlomafota13 shared this article with you from Inoreader Mortalin maintains breast cancer stem cells stemness via activation of Wnt/GSK3beta/beta-catenin signaling pathway Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):2696-2716. eCollection 2021. ABSTRACT Previous research indicated that mortalin overexpressed in breast cancer and contributed to carcinogenesis. Mortalin was also demonstrated to promote Epithelial-mesenchymal transition (EMT) and was considered as a factor for maintaining the stemness of the cancer stem cells. However, the underlying mechanisms about mortalin maintaining the stemness of breast cancer stem cells (BCSCs) remain unclear. Here, we identified that increased expression of mortalin in breast cancer was associated with poorer overall survival rate. Mortalin was elevated in breast cancer cell lines and BCSC-enriched populations. Additionally, knockdown of mortalin significantly inhibited the cell proliferation, migration and EMT, as well as sphere forming capacity and stemness genes expression. Further study revealed that mortalin promoted EMT and maintained BCSCs stemness via activating the Wnt/GSK3β/β-catenin signaling pathway in vivo and in vitro. Taken together, these findings unveiled the mechanism of mortalin in maintaining and regulating the stemness of BCSCs, and may offer novel therapeutic strategies for breast cancer treatment. PMID:34249423 | PMC:PMC8263651 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Monepantel antitumor activity is mediated through inhibition of major cell cycle and tumor growth signaling pathways

xlomafota13 shared this article with you from Inoreader Monepantel antitumor activity is mediated through inhibition of major cell cycle and tumor growth signaling pathways Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3098-3110. eCollection 2021. ABSTRACT In women, epithelial ovarian cancer is the leading cause of gynaecological malignancy-related deaths. Development of resistance to standard platinum and taxane based chemotherapy and recurrence of the disease necessitate development of novel drugs to halt disease progression. An established concept is to target molecular and signaling pathways that substantially contribute to development of drug resistance and disease progression. We have previously shown that, monepantel (MPL) a novel small molecule acetonitrile derivative is highly effective in suppressing growth, proliferation and colony formation of ovarian cancer cells. These effects are achieved through inhibition of the mTOR/p70S6K pathway in cancer cells. The present study was conducted to find in vivo corroboration and explore the effect of MPL om other growth stimulating putative signaling pathways. Here , female nude mice with subcutaneous OVCAR-3 xenografts were treated with 25 and 50 mg/kg doses of MPL administered (IP) three times weekly for 2 weeks. At the doses employed, MPL was modestly effective at suppressing tumor growth, but highly effective in inhibiting, mTOR, P70S6K and 4EBP1. There were also modest reductions in tumor cyclin D1 and retinoblastoma protein expression. Furthermore, it was found that MPL treatment causes down-regulation of IGF-1R, and c-MYC thus unveiling new dimensions to the growing antitumor actions of this potential anticancer drug. MPL treatment led to reduced tumor volume and weights without causing any detectable side effects. Coupled with the recent human safety data published on this molecule, expanded future trials are highly anticipated. PMID:34249447 | PMC:PMC8263694 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Blood-based risk stratification for pre-malignant and symptomatic plasma cell neoplasms to improve patient management

xlomafota13 shared this article with you from Inoreader Blood-based risk stratification for pre-malignant and symptomatic plasma cell neoplasms to improve patient management Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):2736-2753. eCollection 2021. ABSTRACT Standard risk stratification (sRisk) guides clinical management in monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and multiple myeloma (MM). Nonetheless, clinical results are considerably heterogeneous among patients with similar risk status. Blood and bone marrow samples from 276 MGUS, 56 SMM and 242 MM in regular clinical practice were analyzed at diagnosis by flow cytometry. Higher levels of aberrant circulating plasma cells (cPC) (> 0.0035% of leukocytes), combined with albumin, beta2-microglobuline and lactate-dehydrogenase levels, offered minimally-invasive risk stratification (RcPC) with results comparable to sRisk. RcPC and sRisk 10-year progression-free-survival (10y-PFS) rates were: 93.8% vs. 95.1% for low-risk, 78.4% vs. 81.7% for intermediate-risk and 50.0% vs. 47.8% for high-risk MGUS; 58.3% vs. 57.8% l ow-risk, 44.4% vs. 45.8% intermediate-risk and 8.9% vs. 15.0% high-risk SMM; and 44.4% vs. 44.4% low-risk, 36.1% vs. 36.8% intermediate-risk, and 13.3% vs. 16.2% high-risk MM. Circulating-PC > 0.0035% vs. cPC<0.0035% was an independent prognostic factor for PFS (HR=4.389, P=1.2×10-15, Harrell C-statistic =0.7705±0.0190) and over-all survival (OS, HR=4.286, 2.3×10-9, Harrell C-statistic =0.8225±0.0197) that complemented sRisk in patients with low-sRisk (10y-PFS rates 48.1% vs. 87.3%, P=1.2×10-8) and intermediate-sRisk (10y-PFS rates 28.9% vs. 74.1%, P=8.6×10-12). Patients with high cPCs values are associated with higher proliferation and lower apoptosis rates of PC. Circulating-PC > 0.0035% identified MGUS, SMM and MM patients at higher risk of progression or death and predicted a cohort of patients that after relapse from stringent complete response showed shorter OS. These patients could benefit from early consolidation the rapy, tandem ASCT or intensive maintenance. PMID:34249425 | PMC:PMC8263680 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Blinatumomab for HLA loss relapse after haploidentical hematopoietic stem cell transplantation

xlomafota13 shared this article with you from Inoreader Blinatumomab for HLA loss relapse after haploidentical hematopoietic stem cell transplantation Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3111-3122. eCollection 2021. ABSTRACT Loss of patient-specific HLA after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is considered as a relapse mechanism for lacking the incompatible molecule to elicit alloreactivity, which extensively diminishing graft-versus-leukemia (GVL) effects. Blinatumomab, as a CD3/CD19 bispecific antibody, can yield a profound response via redirecting T cells towards malignant lymphoblasts in B-cell acute lymphoblastic leukemia (B-ALL). We aimed to assess the feasibility of blinatumomab in treating patients with HLA loss relapse after haplo-HSCT. Four eligible patients undergoing HLA loss relapse after haplo-HSCT were enrolled in the study. Four patients achieved a complete remission/complete remission with partial he-matologic recovery (CR/CRh) with three minimal residual disease (MRD)-negative response within the first cycle of treatment. Three of th e four met a primary endpoint with CR/CRh and MRD-negative response within 2 cycles of treatment. One patient developed new extramedullary sites of skin after the first cycle. Cytokine release syndrome was observed in one patient. Cytopenias, as well as elevated alanine aminotransferase and aspartate aminotransferase, were two common adverse effects during treatment. By redirecting lysis of CD19-positive lymphoblast who losing the incompatible HLA, blinatumomab is a potential strategy to eradicate malignant cells via restoring GVL effects. A randomized clinical trial assessing blinatumomab in patients with HLA loss relapse after HSCT is warranted. PMID:34249448 | PMC:PMC8263683 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Identification and prognostic analysis of the cetuximab resistance-related gene REV1 in RAS wild-type metastatic colorectal cancer

xlomafota13 shared this article with you from Inoreader Identification and prognostic analysis of the cetuximab resistance-related gene REV1 in RAS wild-type metastatic colorectal cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):2769-2781. eCollection 2021. ABSTRACT The survival of patients with RAS wild-type metastatic colorectal cancer (mCRC) has improved markedly since the introduction of cetuximab, which is an anti-epidermal growth factor receptor monoclonal antibody. However, not all RAS wild-type patients respond to cetuximab treatment. Although some genetic alterations associated with cetuximab resistance have been identified, they cannot fully explain all cases of cetuximab resistance. Thus, in this research, we aimed to identify new genetic alterations associated with resistance to this treatment. The study retrospectively analyzed 70 patients diagnosed with RAS wild-type mCRC at our hospital between November 2009 and July 2018. First, five progression-free survival (PFS)-longest and 5 PFS-shortest tumor deoxyribonucleic acid were analyzed by whole-exome sequencing (WES) to identify differentially mutated gene s. Then, PFS analysis of the 70 patients was used to verify the correlation between the candidate gene and cetuximab sensitivity. Finally, data from public databases were used to further verify the relationship between the mRNA expression level of the candidate gene and cetuximab responsiveness. The WES results indicated REV1: c.2108G > A was a candidate gene mutation related to the effectiveness of cetuximab. Survival analysis suggested REV1: c.2108G > A was associated with rapid disease progression (median PFS time, REV1 mutant vs. REV1 wild-type: 4.4 months vs. 8.7 months, P = 0.034). Data from the Genomics of Drug Sensitivity in Cancer and the Gene Expression Omnibus databases suggested low REV1 mRNA levels might be related to the poor response of CRC cells and reduced cetuximab efficacy among mCRC patients. In conclusion, REV1 expression levels and the REV1: c.2108G > A mutation may be related to cetuximab resistance in RAS< /i> wild-type mCRC. PMID:34249427 | PMC:PMC8263679 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

A novel CT-based radiomic nomogram for predicting the recurrence and metastasis of gastric stromal tumors

xlomafota13 shared this article with you from Inoreader A novel CT-based radiomic nomogram for predicting the recurrence and metastasis of gastric stromal tumors Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3123-3134. eCollection 2021. ABSTRACT Our study aimed to explore the value of applying the CT-based radiomic nomogram for predicting recurrence and/or metastasis (RM) of gastric stromal tumors (GSTs). During the past ten years, a total of 236 patients with GST were analyzed retrospectively. According to the postoperative follow-up classification, the patients were divided into two groups, namely non-recurrence/metastasis group (non-RM) and RM group. All the cases were randomly divided into primary cohort and validation cohort according to the ratio of 7:3. Standardized CT images were segmented by radiologists using ITK-SNAP software manually. Texture features were extracted from all segmented lesions, then radiomic features were selected and the radiomic nomogram was built using least absolute shrinkage and selection operator (LASSO) method. The clinical features with the greatest correlation with RM of GST were selected by univariate analysis, and used as parameters to build the clinical feature model. Eventually, model of radiomic and clinical features were fitted to construct the clinical + radiomic feature model. The performance of each model was evaluated by the area under receiver operating characteristic (ROC) curve (AUC). A total of 1223 features were extracted from all the segmentation regions of each case, and features were selected via the least absolute shrinkage and LASSO binary logistic regression model. After deletion of redundant features, four key features were obtained, which were used as the parameters to build a radiomic signature. The AUCs of radiomic nomogram in primary cohort and validation cohort were 0.816 and 0.946, respectively. The AUCs of clinical + radiomic feature model in primary cohort and validation cohort were 0.833 and 0.937, respectively. Using DeLong test, the differences of AUC values between radiomic nomogram and clinical + radiomic featur e model in primary cohort (P = 0.840) and validation cohort (P = 0.857) were not statistically significant. To sum up, CT-based radiomic nomogram is of great potential in predicting the RM of GST non-invasively before operation. PMID:34249449 | PMC:PMC8263673 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

MiR-19b-3p and miR-101-3p as potential biomarkers for prostate cancer diagnosis and prognosis

xlomafota13 shared this article with you from Inoreader MiR-19b-3p and miR-101-3p as potential biomarkers for prostate cancer diagnosis and prognosis Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):2802-2820. eCollection 2021. ABSTRACT Prostate cancer (PCa) is the most commonly diagnosed male malignancy worldwide. Early diagnosis and metastases detection are crucial features to diminish patient mortality. High fat diet (HFD) and metabolic syndrome increase PCa risk and aggressiveness. Our goal was to identify miRNAs-based biomarkers for PCa diagnosis and prognosis associated with HFD. Mice chronically fed with a HFD or control diet (CD) were subcutaneously inoculated with androgen insensitive PC3 cells. Xenografts from HFD-fed mice showed increased expression of 7 miRNAs that we named "candidates" compared to CD-fed mice. These miRNAs modulate specific metabolic and cancer related pathways. Using bioinformatic tools and human datasets we found that hsa-miR-19b-3p and miR-101-3p showed more than 1,100 validated targets involved in proteoglycans in cancer and fatty acid biosynthesis. These miRNAs were significantly increased in the bloodstream of PCa patients compared to non-PCa volunteers, and in prostate tumors compared to normal adjacent tissues (NAT). Interestingly, both miRNAs were also increased in tumors of metastatic patients compared to tumors of non-metastatic patients. Further receiver-operating characteristic (ROC) analysis determined that hsa-miR-19b-3p and hsa-miR-101-3p in serum showed poor predictive power to discriminate PCa from non-PCa patients. Hsa-miR-19b-3p showed the best score to discriminate between tumor and NAT, while hsa-miR-101-3p was useful to differentiate between metastatic and non-metastatic PCa patients. Hsa-miR-101-3p was increased in exosomes isolated from blood of PCa patients. Although more detailed functional exploration and validation of the molecular mechanisms are required, we identified hsa-miR-19b-3p and hsa-miR-101-3p with high potential for PCa diagnosis and prognosis. PMID:34249429 | PMC:PMC8263646 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Methionyl-tRNA synthetase and aminoacyl-tRNA synthetases interacting multi-functional protein-lacking exon 2 as potential diagnostic biomarkers for lung cancer

xlomafota13 shared this article with you from Inoreader Methionyl-tRNA synthetase and aminoacyl-tRNA synthetases interacting multi-functional protein-lacking exon 2 as potential diagnostic biomarkers for lung cancer Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):3135-3144. eCollection 2021. ABSTRACT Cytological specimens from computed tomography (CT)-guided needle aspiration biopsy (CT-NAB) have relatively low sensitivity for lung cancer diagnosis. This study evaluated the usefulness of the dual immunofluorescence (IF) staining method using methionyl-tRNA synthetase (MARS), aminoacyl-tRNA synthetases interacting multi-functional protein-lacking exon 2 (AIMP2-DX2), and pan-cytokeratin (pan-CK) obtained from clinical specimens. One-hundred forty-five cytology specimens were prospectively collected from patients who underwent CT-NAB under the suspicion of lung cancer. The results of two combinations of MARS, AIMP2-DX2, and pan-CK dual IF staining were compared with those of conventional cytology by calculating the area under the curve (AUC). The results of combining dual IF with conventional cytology showed higher AUC than conventional cytology alone: cytology/M ARS/AIMP2-DX2 (0.891 vs. 0.829, P = 0.003), cytology/MARS/pan-CK (0.916 vs. 0.829, P < 0.001), and cytology/AIMP2-DX2/pan-CK (0.877 vs. 0.829, P = 0.005). In specimens with non-diagnostic results in conventional cytology, MARS/AIMP2-DX2 dual IF staining showed sensitivity, specificity, and AUC of 60.0%, 86.4%, and 0.79, respectively. The dual IF staining method using two combinations of MARS, AIMP2-DX2, and pan-CK is an effective diagnostic tool that can improve the lung cancer diagnostic yield by complementing conventional cytology. PMID:34249450 | PMC:PMC8263685 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

NONO phase separation enhances DNA damage repair by accelerating nuclear EGFR-induced DNA-PK activation

xlomafota13 shared this article with you from Inoreader NONO phase separation enhances DNA damage repair by accelerating nuclear EGFR-induced DNA-PK activation Via American Journal of Cancer Research Am J Cancer Res. 2021 Jun 15;11(6):2838-2852. eCollection 2021. ABSTRACT Radioresistance is one of the main causes of cancer treatment failure, which leads to relapse and inferior survival outcome of cancer patients. Liquid-liquid phase separation (LLPS) of proteins is known to be involved in various biological processes, whereas its role in the regulation of radiosensitivity remains largely unknown. In this study, we characterized NONO, an RNA/DNA binding protein with LLPS capacity, as an essential regulator of tumor radioresistance. In vitro assay showed that NONO involved in DNA repair via non-homologous end joining (NHEJ) manner. NONO knockout significantly reduced DNA damage repair and sensitized tumor cells to irradiation in vitro and in vivo. NONO overexpression was correlated with an inferior survival outcome in cancer patients. Mechanically, NONO was associated with nuclear EGFR (nEGFR). Both irradiation and EGF treatment indu ced nEGFR accumulation, thereby increased the association between NONO and nEGFR. However, NONO was not a substrate of EGFR kinase. Furthermore, NONO promoted DNA damage-induced DNA-PK phosphorylation at T2609 by enhancing the interaction between EGFR and DNA-PK. Importantly, NONO protein formed high concentration LLPS droplets in vitro, and recruited EGFR and DNA-PK. Disruption of NONO droplets with LLPS inhibitor significantly reduced the interaction between EGFR and DNA-PK, and suppressed DNA damage-induced phosphorylation of T2609-DNA-PK. Taken together, LLPS of NONO recruits nuclear EGFR and DNA-PK and enhances their interaction, further increases DNA damage-activated pT2609-DNA-PK and promotes NHEJ-mediated DNA repair, finally leads to tumor radioresistance. NONO phase separation-mediated radioresistance may serve as a novel molecular target to sensitize tumor cell to radiotherapy. PMID:34249431 | PMC:PMC8263645 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.