TMUB1 as a diagnostic and prognostic marker for colorectal cancer

BackgroundTransmembrane and ubiquitin-like domain-containing protein 1 (TMUB1) is overexpressed in a large number of liver and esophageal tumors. However, only a few reports on the clinical significance of TMUB1 in colorectal cancer (CRC) exist. MethodsHere, we evaluated the clinical significance and potential biological role of TMUB1 using bioinformatics analysis. Univariate and multivariate analyses were performed to evaluate the relationship of TMUB1 with clinicopathological features. Gene set enrichment analysis (GSEA) was performed to identify the biological function of TMUB1, while any associations between the expression of TMUB1 and the infiltration of 24 immune cells were analyzed using imple-sample GSEA. ResultsTMUB1 was significantly overexpressed in CRC tissues compared with normal controls. High expression of TMUB1 in CRC was associated with T stage, neotype, and residual tumor. Moreover, TMUB1 was identified as an independent factor of poor disease-free survival (DFS) and short overall survival (OS). GSEA demonstrated that TMUB1 was related to hypoxia, angiogenesis, adipogenesis, inflammatory response, IL6-JAK-STAT3 signaling, apoptosis, mitotic spindle, and IL2-STAT5 signaling. The expression of TMUB1 negatively correlated with the abundance of T helper cells, Tcm cells, macrophages, and Th2 cells, whereas it positively correlated with the abundance of several immune cell types, including CD56bright and CD56dim NK cells. ConclusionsTMUB1 may be a potential diagnostic and prognosis biomarker for colorectal cancer

Plasma IL-8 and ICOSLG as prognostic biomarkers in glioblastoma

Background CNS immune privilege has been challenged in recent years. Glioblastoma (GBM) immune dysfunction includes complex interactions with the immune system outside the CNS. The aim of this study was to determine diagnostic and prognostic potential of immune-related proteins in plasma in GBM and interrogate biomarker presence in the brain tumor microenvironment (TME). Methods 158 patients with glioma WHO grade II–IV were included. Plasma collected at surgery was screened for 92 proteins using proximity extension assay technology and related to clinical outcome. Secretion and expression of candidate prognostic biomarkers were subsequently analyzed in 8 GBM cell lines and public RNAseq data. Results Plasma levels of 20 out of 92 screened proteins were significantly different in patients with GBM compared to patients with astrocytoma WHO grade II–III. High plasma IL-8 (HR=1.52; P=0.0077) and low CD244 (HR=0.36; P=0.0004) were associated with short progression-free survival (PFS) and high plasma IL-8 (HR=1.40; P=0.044) and low ICOS ligand (ICOSLG) (HR=0.17; P=0.0003) were associated with short overall survival (OS) in newly diagnosed patients with GBM. A similar trend was found for ICOSLG (HR=0.34; P=0.053) in recurrent GBM. IL-8 was mostly secreted and expressed by mesenchymal GBM cell lines and expressed by vascular cells and immune cells in the TME. This was also the case for ICOSLG, although less consistent, and with additional expression in tumor-associated oligodendrocytes. Conclusions High plasma IL-8 and low ICOSLG at surgery are associated with short OS in newly diagnosed GBM. Source of plasma ICOSLG may be found outside the TME.

Multidimensional study of CDCA family members in gastric carcinoma with prognostic value

Gastric cancer (GC) represents a widespread malignancy, having a poor prognosis, making it necessary to search for reliable biomarkers. Cell Division Cycle Associated protein (CDCA) family, comprising CDCA1-8, acts as a key in tumor progression. However, CDCAs expression and their impact on prognosis in gastric cancer, especially stomach adenocarcinoma (STAD), have not been clarified. Consequently, we carried out a multifaceted study aimed at exploring the CDCAs expression levels and appraising their potential prognostic values in patients with STAD, using bioinformatic tools. Remarkable upregulation of all 8 CDCAs was identified in STAD tissues, as compared with the healthy tissues. Elevated CDCA4/7/8 mRNA expression predicted a short overall survival (OS), while STAD patients, showing increased transcriptional levels of CDCA7, exhibited a short disease-free survival (DFS). The most frequent alteration was low mRNA expression among all mutations. The function enrichment analysis incorporating Gene Ontology (GO) together with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway showed that cell cycle, foxO signaling pathway and Epstein-Barr virus were relevant to the main functions of CDCAs. Finally, through the immune infiltration analysis, a remarkable relationship was found between CDCAs expression and the extent of infiltrating levels in six immunocytes. Therefore, differentially expressed CDCAs were assessed as potential biomarkers of the prognosis of STAD patients, aiming at the improved survival of these patients. Furthermore, this study might offer new ideas for the design and development of immunotherapeutic drugs.

Inhibition of CPT1a as a prognostic marker can synergistically enhance the antileukemic activity of ABT199

Background Fatty acid oxidation (FAO) provides an important source of energy to promote the growth of leukemia cells. Carnitine palmitoyltransferase 1a(CPT1a), a rate-limiting enzyme of the essential step of FAO, can facilitate cancer metabolic adaptation. Previous reports demonstrated that CPT1a acts as a potential molecular target in solid tumors and hematologic disease. However, no systematic study was conducted to explore the prognostic value of CPT1a expression and possible treatment strategies with CPT1a inhibitor on acute myeloid leukemia (AML). Methods The expression of CPT1a in 325 cytogenetically normal AML (CN-AML) patients was evaluated using RT-PCR. The combination effects of ST1326 and ABT199 were studied in AML cells and primary patients. MTS was used to measure the cell proliferation rate. Annexin V/propidium iodide staining and flow cytometry analysis was used to measure the apoptosis rate. Western blot was used to measure the expression of Mcl-1. RNAseq and GC-TOFMS were used for genomic and metabolic analysis. Results In this study, we found AML patients with high CPT1a expression (n = 245) had a relatively short overall survival (P = 0.01) compared to patients in low expression group (n = 80). In parallel, downregulation of CPT1a inhibits proliferation of AML cells. We also conducted genomic and metabolic interactive analysis in AML patients, and found several essential genes and pathways related to aberrant expression of CPT1a. Moreover, we found downregulation of CPT1a sentitized BCL-2 inhibitor ABT199 and CPT1a-selective inhibitor ST1326 combined with ABT199 had a strong synergistic effect to induce apoptosis in AML cells and primary patient blasts for the first time. The underlying synergistic mechanism might be that ST1326 inhibits pGSK3β and pERK expression, leading to downregulation of Mcl-1. Conclusion Our study indicates that overexpression of CPT1a predicts poor clinical outcome in AML. CPT1a-selective inhibitor ST1326 combined with Bcl-2 inhibitor ABT199 showed strong synergistic inhibitory effects on AML.

Inhibition of CPT1a as a Prognostic Marker can Synergistically Enhance the Antileukemic Activity of ABT199

Background Fatty acid oxidation (FAO) provides an important source of energy to promote the growth of leukemia cells. Carnitine palmitoyltransferase 1a(CPT1a), a rate-limiting enzyme of the essential step of FAO, can facilitate cancer metabolic adaptation. Previous reports demonstrated that CPT1a acts as a potential molecular target in solid tumors and hematologic disease. However, no systematic study was conducted to explore the its prognostic value and possible treatment strategies on acute myeloid leukemia (AML). Methods The expression of CPT1a in 325 cytogenetically normal AML (CN-AML) cases was evaluated using RT-PCR. The combination effects of ST1326 and ABT199 were studied in AML cells and primary patients. MTS was used to measure the cell proliferation rate. Annexin V/propidium iodide staining and flow cytometry analysis was used to measure the apoptosis rate. western blot were used to measure the expression of Mcl-1. RNAseq and GC-TOFMS were used for genomic and metabolic analysis. Results In this study, we found AML patients with high CPT1a expression (n = 245) had a relatively short overall survival (P = 0.01) and event free survival (P = 0.032) compared to patients in low expression group (n = 80). In parallel, downregulation of CPT1a inhibits proliferation of AML cells. We also conducted genomic and metabolic interactive analysis in AML patients, and found several essential genes and pathways related to aberrant expression of CPT1a. Moreover, we found downregulation of CPT1a sentitizes BCL-2 inhibitor ABT199 and CPT1a-selective inhibitor ST1326 combined with ABT199 has a strong synergistic effect to induce apoptosis in AML cells and primary patient blasts for the first time. The underlying synergistic mechanism might be that ST1326 inhibits pGSK3β and pERK expression, leading to downregulation of Mcl-1. Conclusion Our study indicates that overexpression of CPT1a predicts poor clinical outcome in AML. CPT1a-selective inhibitor ST1326 combined with Bcl-2 inhibitor ABT199 showed strong synergistic inhibitory effects on AML.

Inhibition of CPT1a as a Prognostic Marker can Synergistically Enhance the Antileukemic Activity of ABT199

Background: Fatty acid oxidation (FAO) provides an important source of energy to promote the growth of leukemia cells. Carnitine palmitoyltransferase 1a(CPT1a), a rate-limiting enzyme of the essential step of FAO, can facilitate cancer metabolic adaptation. Previous reports demonstrated that CPT1a acts as a potential molecular target in solid tumors and hematologic disease. However, no systematic study was conducted to explore the its prognostic value and possible treatment strategies on acute myeloid leukemia (AML).Methods: The expression of CPT1a in 325 cytogenetically normal AML (CN-AML) cases was evaluated using RT-PCR. The combination effects of ST1326 and ABT199 were studied in AML cells and primary patients. MTS was used to measure the cell proliferation rate. Annexin V/propidium iodide staining and flow cytometry analysis was used to measure the apoptosis rate. western blot were used to measure the expression of Mcl-1.Results: In this study, we found AML patients with high CPT1a expression (n = 245) had a relatively short overall survival (P =0.01) and event free survival (P=0.032) compared to patients in low expression group (n =80). In parallel, downregulation of CPT1a inhibits proliferation of AML cells. We also performed a metabolomic analysis and observed a decrease of fatty acid in CPT1a high expression group comparing to low expression group, which confirms that CPT1a can facilitate FAO to provide energy fueling tumor growth. Moreover, we found downregulation of CPT1a sentitizes BCL-2 inhibitor ABT199 and CPT1a-selective inhibitor ST1326 combined with ABT199 has a strong synergistic effect to induce apoptosis in AML cells and primary patient blasts for the first time. The underlying synergistic mechanism might be that ST1326 inhibits pGSK3β and pERK expression, leading to downregulation of Mcl-1.Conclusion: our study indicates that overexpression of CPT1a predicts poor clinical outcome in AML. CPT1a-selective inhibitor ST1326 combined with Bcl-2 inhibitor ABT199 showed strongsynergistic inhibitory effects on AML.

Key Enzymes in Pyrimidine Synthesis, CAD and CPS1, Predict Prognosis in Hepatocellular Carcinoma

Patients with hepatocellular carcinoma (HCC) have a highly variable clinical course. Therefore, there is an urgent need to identify new prognostic markers to determine prognosis and select specific therapies. Recently, it has been demonstrated that dysregulation of the urea cycle (UC) is a common phenomenon in multiple types of cancer. Upon UC dysregulation, nitrogen is diverted toward the multifunctional enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD), and increases pyrimidine synthesis. In this study, we investigated the role of CAD and carbamoyl-phosphate synthetase 1 (CPS1), a rate-limiting enzyme of the UC highly expressed in hepatocytes, in HCC. We created a tissue microarray to analyze expression of both enzymes by immunohistochemistry in a large and well-characterized overall cohort of 871 HCCs of 561 patients that underwent surgery. CAD was induced in recurrent HCCs, and high expression predicted shorter overall survival. CPS1 was downregulated in HCC and further reduced in recurrent tumors and distant metastases. Additionally, low CPS1 was associated with short overall survival. A combined score of both enzymes was an independent prognostic marker in a multivariate Cox regression model (HR = 1.37, 95% confidence interval 1.06–1.75, p = 0.014). Inhibition of pyrimidine synthesis may represent a novel therapeutic strategy for HCC.