Genomics and prognosis analysis of epithelial-mesenchymal transition in colorectal cancer patients

Cancer shared this article with you from Inoreader Genomics and prognosis analysis of epithelial-mesenchymal transition in colorectal cancer patients Via Latest Results for BMC Cancer Abstract Background The epithelial-mesenchymal transition (EMT) plays a pivotal role in various physiological processes, such as embryonic development, tissue morphogenesis, and wound healing. EMT also plays an important role in cancer invasion, metastasis, and chemoresistance. Additionally, EMT is partially responsible for chemoresistance in colorectal cancer (CRC). The aim of this research is to develop an EMT-based prognostic signature in CRC. Methods RNA-seq and microarray data, together with clinical information, were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. A total of 244 differentially expressed EMT-related genes (ERGs) were obtained by comparing the expression between normal and tumor tissues. An EMT-related signature of 11 genes was identified as crucially related to the overall survival (OS) of patients through univariate Cox proportional hazard analysis, least absolute shrinkage and selection operator (LASSO), and Cox regression analysis. Finally, we established a clinical nomogram to predict the survival possibility of CRC patients by integrating clinical characteristics and the EMT-related gene signature. Results Two hundred and forty-four differentially expressed ERGs and their enriched pathways were confirmed. Significant enrichment analysis revealed that EMT-related signaling pathway genes were highly related to CRC. Kaplan-Meier analysis revealed that the 11-EMT signature could significantly distinguish high- and low-risk patients in both TCGA and GEO CRC cohorts. In addition, the calibration curves verified fine concordance between the nomogram prediction model and actual observation. Conclusion We developed a novel EMT-related gene signature for the prognosis prediction of CRC patients, which could improve the individualized outcome prediction in CRC. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Overriding sorafenib resistance via blocking lipid metabolism and Ras by sphingomyelin synthase 1 inhibition in hepatocellular carcinoma

Cancer shared this article with you from Inoreader Overriding sorafenib resistance via blocking lipid metabolism and Ras by sphingomyelin synthase 1 inhibition in hepatocellular carcinoma Via Latest Results for Cancer Chemotherapy and Pharmacology Abstract Background The survival benefit of sorafenib, the most used drug for advanced hepatocellular carcinoma (HCC), is unsatisfactory due to the development of adaptive resistance. Exploring the mechanisms underlying sorafenib resistance is important to develop sensitizing strategy. Sphingomyelin synthase (SMS) plays a critical role in sphingolipid metabolism which is involved in oncogenesis and drug resistance. Methods SMS1 and SMS2 levels in HCC cells in response to prolonged chemotherapy were analyzed using ELISA. mRNA and protein levels of SMS in HCC and adjacent normal tissues were analyzed by ELISA and real-time PCR. The roles of SMS and its downstream targets were investigated using cellular and biochemical assays and mass spectrometry. Results SMS1, but not SMS2, was upregulated in HCC in response to sorafenib treatment, although HCC displayed similar RNA and protein level of SMS1 compared to adjacent normal liver tissues. Overexpression of SMS1 promoted HCC growth and migration, and alleviated sorafenib's toxicity. SMS1 inhibition via genetic and pharmacological approaches consistently resulted in inhibition of growth and migration, and apoptosis induction in sorafenib-resistance HCC cells. SMS1 inhibition also augmented the efficacy of sorafenib in sensitive HCC cells. SMS1 inhibition disrupted sphingolipid metabolism via accumulating ceramide and decreasing sphingomyelin, inducing mitochondrial dysfunction and oxidative stress, and decreasing Ras activity in resistant cells. Overexpression of constitutively active Ras reversed the inhibitory effects of SMS1 inhibition. Although SMS1 overexpression did not affect Ras expression and activity, Pearson correlation coefficient analysis of SMS1 and Ra s expression demonstrated that there was positive correlation between SMS1 and RAS (NRAS, R = 0.55, p < 0.01; KRAS, R = 0.44, p < 0.01). Conclusions Our work is the first to suggest that SMS1 plays a more important role in sorafenib resistance than tumorigenesis, and provides preclinical evidence to overcome sorafenib resistance with SMS1 inhibition in HCC. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Development and validation of an RNA binding protein-associated prognostic model for hepatocellular carcinoma

Cancer shared this article with you from Inoreader Development and validation of an RNA binding protein-associated prognostic model for hepatocellular carcinoma Via Latest Results for BMC Cancer Abstract Background Hepatocellular carcinoma (HCC) is among the deadliest forms of cancer. While RNA-binding proteins (RBPs) have been shown to be key regulators of oncogenesis and tumor progression, their dysregulation in the context of HCC remains to be fully characterized. Methods Data from the Cancer Genome Atlas - liver HCC (TCGA-LIHC) database were downloaded and analyzed in order to identify RBPs that were differentially expressed in HCC tumors relative to healthy normal tissues. Functional enrichment analyses of these RBPs were then conducted using the GO and KEGG databases to understand their mechanistic roles. Central hub RBPs associated with HCC patient prognosis were then detected through Cox regression analyses, and were incorporated into a prognostic model. The prognostic value of this model was then assessed through the use of Kaplan-Meier curves, time-related ROC analyses, univariate and multivariate Cox regression analyses, and nomograms. Lastly, the relationship between individual hub RBPs and HCC patient overall survival (OS) was evaluated using Kaplan-Meier curves. Finally, find protein-coding genes (PCGs) related to hub RBPs were used to construct a hub RBP-PCG co-expression network. Results In total, we identified 81 RBPs that were differentially expressed in HCC tumors relative to healthy tissues (54 upregulated, 27 downregulated). Seven prognostically-relevant hub RBPs (SMG5, BOP1, LIN28B, RNF17, ANG, LARP1B, and NR0B1) were then used to generate a prognostic model, after which HCC patients were separated into high- and low-risk groups based upon resultant risk score values. In both the training and test datasets, we found that high-risk HCC patients exhibited decreased OS relative to low-risk patients, with time-dependent area under the ROC curve values of 0.801 and 0.676, respectively. This model thus exhibited good prognostic performance. We additionally generated a prognostic nomogram based upon these seven hub RBPs and found that four other genes were significantly correlated with OS. Conclusion We herein identified a seven RBP signature that can reliably be used to predict HCC patient OS, underscoring the prognostic relevance of these genes. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

STAT3 regulates miR93-mediated apoptosis through inhibiting DAPK1 in renal cell carcinoma

Cancer shared this article with you from Inoreader STAT3 regulates miR93-mediated apoptosis through inhibiting DAPK1 in renal cell carcinoma Via Cancer Gene Therapy - Issue - nature.com science feeds Cancer Gene Therapy, Published online: 23 November 2020; doi:10.1038/s41417-020-00235-y STAT3 regulates miR93-mediated apoptosis through inhibiting DAPK1 in renal cell carcinoma View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Optimizing the use of telemedicine in oncology care: post-pandemic opportunities

Cancer shared this article with you from Inoreader Optimizing the use of telemedicine in oncology care: post-pandemic opportunities Via Clinical Cancer Research Online First Articles Utilization of telehealth as part of the cancer care delivery continuum dramatically escalated in response to the COVID-19 pandemic at major cancer centers across the globe. The rapid shift toward telehealth visits for non-treatment cancer care provided immediate benefit through reducing unnecessary risk of exposure, overcoming transportation barriers faced by both patients and caregivers, and fast-tracking care transformation. As such, delineating the impact of telehealth on access, health equity, quality, and outcomes will be essential for refining the use of digital strategies and telehealth toward optimizing cancer care. Herein, experiences to date with telehealth usage for oncology care is reviewed, and priorities outlined for post-pandemic opportunities to improve the lives of cancer patients through telemedicine. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Safety and clinical activity of a new anti-PD-L1 antibody as monotherapy or combined with targeted therapy in advanced solid tumors: the PACT phase Ia/Ib trial

Cancer shared this article with you from Inoreader Safety and clinical activity of a new anti-PD-L1 antibody as monotherapy or combined with targeted therapy in advanced solid tumors: the PACT phase Ia/Ib trial Via Clinical Cancer Research Online First Articles Purpose: This phase Ia/Ib PACT study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of a new PD-L1 inhibitor, LY3300054, as monotherapy or in combination with ramucirumab, abemaciclib, or merestinib (a type II MET kinase inhibitor) in patients with advanced, refractory solid tumors (NCT02791334). Patients and methods: Patients were enrolled into cohorts of escalating LY3300054 dose (phase Ia) as monotherapy (N=15) or combined with ramucirumab (N=10), abemaciclib (N=24), or merestinib (N=12). The phase Ib dose expansion enrolled eight patients with melanoma in the monotherapy arm and 12 patients with pancreatic cancer in the merestinib combination arm. Combination treatments were administered concurrently from day 1 of each cycle. A 14-day lead-in abemaciclib arm was also explored. Primary endpoints were dose-limiting toxicity (DLT) and safety. Results: Treatment-related adverse events included fatigue and nausea in the mon otherapy arm (13% for each), hypothyroidism (30%) in the ramucirumab arm, diarrhea (54%) in the abemaciclib arm, and nausea (25%) in the merestinib arm. DLTs associated with hepatoxicity were observed in three of four patients in the abemaciclib lead-in cohorts. No DLTs or grade 3 or 4 hepatoxicity were reported in the concurrent abemaciclib arm. Pharmacokinetic characteristics were comparable to other PD-L1 inhibitors. One patient in each arm experienced a partial response per RECIST v1.1 lasting ≥7 months. Conclusions: LY3300054 was well tolerated without unexpected safety concerns when administered alone or concurrently with ramucirumab, abemaciclib, or merestinib. Lead-in abemaciclib before combining with LY3300054 was not feasible due to hepatotoxicity. Durable clinical benefits were seen in all regimens. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Combined Inhibition of G{alpha}q and MEK Enhances Therapeutic Efficacy in Uveal Melanoma.

Cancer shared this article with you from Inoreader Combined Inhibition of G{alpha}q and MEK Enhances Therapeutic Efficacy in Uveal Melanoma. Via Clinical Cancer Research Online First Articles Purpose: All uveal melanoma and a fraction of other melanoma subtypes are driven by activation of the Gαq pathway. Targeting these melanomas has proven difficult despite advances in the molecular understanding of key driver signaling pathways in the disease pathogenesis. Inhibitors of Gαq have shown promising preclinical results, but their therapeutic activity in distinct Gαq mutational contexts and in vivo have remained elusive. Experimental Design: We used an isogenic melanocytic cellular system to systematically examine hotspot mutations in GNAQ (e.g., G48V, R183Q, Q209L) and CYSLTR2 (L129Q) found in human uveal melanoma. This cellular system and human uveal melanoma cell lines were used in vitro and in vivo xenograft studies to assess the efficacy of Gαq inhibition as a single agent and in combination with MEK inhibition. Results: We demonstrate that the Gαq inhibitor YM-254890 inhibited downstream signaling and in vitro growth in all mutants. In vivo, YM-254890 slowed tumor growth but did not cause regression in human uveal melanoma xenografts. Through comprehensive transcriptome analysis, we observed that YM-254890 caused inhibition of the MAPK signaling with evidence of rebound by 24 hours and combination treatment of YM-254890 and a MEK inhibitor led to sustained MAPK inhibition. We further demonstrate that the combination caused synergistic growth inhibition in vitro and tumor shrinkage in vivo. Conclusions: These data suggest that the combination of Gαq and MEK inhibition provides a promising therapeutic strategy and improved therapeutic window of broadly targeting Gαq in uveal melanoma. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.