Downregulation of ACSM3 promotes metastasis and predicts poor prognosis in hepatocellular carcinoma.
Ruan Hao-Yu,Yang Chen,Tao Xue-Mei,He Jia,Wang Ting,Wang Hui,Wang Cun,Jin Guang-Zhi,Jin Hao-Jie,Qin Wen-Xin
American journal of cancer research
Understanding mechanisms of cancer metastasis is crucial for reduction of cancer mortality. Acyl-CoA medium-chain synthetase 3 (ACSM3) is an acyl-CoA synthetase which takes part in the first step of fatty acid metabolism. However, the expression, clinical significance and biological function of ACSM3 remain unknown in hepatocellular carcinoma (HCC). In this study, the expression and prognostic relevance of ACSM3 were investigated by tissue microarray and HCC clinical samples. Migration and invasion assays were carried out for functional analysis in vitro and a xenograft model was used to analyze the effects of ACSM3 on cancer metastasis in vivo. Furthermore, human phospho-kinase array assays were performed to explore molecular mechanisms of ACSM3 in HCC. The results showed ACSM3 was downregulated in HCC tissues. HCC patients with low expression of ACSM3 exhibited poor prognosis. Overexpression of ACSM3 attenuated migration and invasion of HCC cells and and downregulated the phosphorylation of WNK1 and AKT. Our findings indicate ACSM3 is a novel prognostic marker and a potential therapeutic target for HCC.
Integrative transcriptome analysis of liver cancer profiles identifies upstream regulators and clinical significance of ACSM3 gene expression.
Gopal Ramani,Selvarasu Karthikeyan,Pandian Ponmathi Panneer,Ganesan Kumaresan
Cellular oncology (Dordrecht)
PURPOSE:Hepatocellular carcinoma (HCC) is one of the most common human malignancies. It has frequently been associated with metabolic perturbations and liver damages. Various members of the family of acyl-CoA synthetases are known to be involved in the production of bioactive fatty acids, and altered expression of its encoding genes has been found to be involved in metabolic perturbations. For the development of novel diagnostic and therapeutic HCC options, a fundamental understanding of the mechanisms associated with the deregulation of candidate genes involved in metabolic perturbation is required. METHODS:A meta-analysis of multiple HCC mRNA profiles was performed to identify consistently deregulated genes. Expression of the acyl-CoA synthetase medium chain family member 3 (ACSM3) gene was subsequently assessed in different HCC tumor stages and correlated with various clinicopathological features. Transcription regulation, survival and pathway-associated features of the ACSM3 gene were investigated using integrative functional genomic and molecular cell biological methods. RESULTS:We found that expression of the ACSM3 gene was significantly reduced in HCC tissues and was frequently downregulated in patients exhibiting high alpha-fetoprotein (AFP) levels, high alanine aminotransferase (ALT) levels, multiple nodules and large tumors. Loss of ACSM3 expression was found to correlate with advanced HCC stages and a poor survival. In addition, HNF4α was found to positively regulate the expression of the ACSM3 gene, while PPARγ was found to transcriptionally repress it. Downregulation of ACSM3 expression was perceived upon activation of the TGFβ, WNT, AKT and MYC signalling pathways. In addition, we found that ACSM3 expression correlates with fatty acid oxidation in HCC. CONCLUSION:Our data provide evidence for a differential expression and regulation of the ACSM3 gene in HCC, and may lay a foundation for therapeutically targeting fatty acid metabolism in these tumors.
10.1007/s13402-017-0321-0
Loss of ACSM3 confers worsened prognosis and immune exclusion to cutaneous melanoma.
Zhu Zhidong,Wang Duoqin,Shen Yanyun
Journal of Cancer
Malignant melanoma (MM) is a highly aggressive cutaneous cancer with undetermined underlying genetic disposition. We aim to evaluate prognostic and mechanistic role of ACSM3 in MM. In silico reproduction of TCGA MM dataset, GEO dataset, GDSC dataset and human protein atlas was performed to establish differential expression of ACSM3. In vitro and in vivo validation using A375 and SKMEL1 MM cells were performed to profile tumorigenic role and functional attribution of the gene. ACSM3 expression was significantly downregulated in MM. Lower expression of ACSM3 conferred worsened prognosis of MM. Lower ACSM3 was observed in Asian ethnicity. Knock-down (KD) and overexpression (OE) of ACSM3 resulted in significant increased and decreased proliferation, invasion and colony formation in MM cells, respectively. Pathway annotation revealed significantly active immune response invoked by ACSM3. Lower ACSM3 expression was associated with decreased CD8+, macrophage and dendritic cell infiltration. Cox regression revealed loss of survival contribution of ACSM3 in the presence of immune infiltrates supporting immune regulatory role of ACSM3. Drug sensitivity analysis revealed BRAF inhibitor PLX-4720 was sensitive in both MM cells. ACSM3 expression showed no correlation with immune checkpoint molecules. Combined ACSM3-OE and PLX-4720 in MM cells showed synergistic inhibition in MM cells and xenograft murine models with no significant toxicity. Loss of ACSM3 was associated with poor prognosis in MM. Overexpression of ACSM3 synergistically inhibited MM with PLX-4720. ACSM3 was potentially associated with immune exclusion in MM. Further validation was warranted in future studies.
10.7150/jca.48354
The Overexpression of Suppresses the Ovarian Cancer Progression the Inhibition of Integrin β1/AKT Signaling Pathway.
Yan Limei,He Zeping,Li Wei,Liu Ning,Gao Song
Frontiers in oncology
Ovarian cancer is considered as one of the most fatal gynecologic malignancies. This work aimed to explore the effects and regulatory mechanism of (, a subunit of CoA ligases) in ovarian cancer progression. As well as employing CCK-8 assay, clone formation assay, and cell cycle analysis were carried out to investigate cell proliferation ability. Wound healing assay and transwell assay were subsequently used to assess cell migration and invasion. Mice xenografts were then conducted to measure the effects of on tumor development . Our bioinformatics analysis suggested that the expression of was down-regulated in ovarian cancer tissues, and the low expression level of might related with poorer overall survival than high mRNA expression of in ovarian cancer patients. We artificially regulated the expression of to evaluate its effects on ovarian cancer malignant phenotypes. Our data revealed that the overexpression of inhibited cell proliferation, migration, and invasion of ovarian cancer cells. In contrast, the knock-down of received the opposite results. Our western blot results showed that the Integrin β1/AKT signaling pathway was negatively regulated by expression. Moreover, overexpression-induced suppression of cell migration and invasion activities were abolished by the overexpression of (Integrin β1). Additionally, the growth of ovarian cancer xenograft tumors was also repressed by the overexpression of . And interference obtained the contrary effects . In summary, acts as a tumor suppressor gene and may be a potential therapeutic target of ovarian cancer.
10.3389/fonc.2021.644840
Predicting Panel of Metabolism and Immune-Related Genes for the Prognosis of Human Ovarian Cancer.
Frontiers in cell and developmental biology
OBJECTIVE:Ovarian cancer (OC) is a high deadly gynecologic cancer with a poor prognosis. The identification of genomic aberrations could predict the clinical prognosis of OC patients and may eventually develop new therapeutic strategies in the future. The purpose of this study is to create comprehensive co-expressed gene networks correlated with metabolism and the immune process of OC. METHODS:The transcriptome profiles of TCGA OC datasets and GSE26193 datasets were analyzed. The mRNA expression level, hub genomic alteration, patient's survival status, and tumor cell immune microenvironment of metabolism-related genes were analyzed from TCGA, GTEX, Oncomine, Kaplan-Meier Plotter, cBioPortal, TIMER, ESTIMATE, and CIBERSORT databases. We further validated the mRNA and protein expression levels of these hub genes in OC cell lines and tissues using qRT-PCR and immunohistochemistry. RESULTS:The LASSO-Cox regression analyses unveiled seven differently expressed metabolism-related genes, including , and . The Cox regression risk model could be served as an independent marker to predict the overall clinical survival of OC patients. The expression of GFPT2, DGKD, ACACB, and ACSM3 were downregulated in OC tissues, while IDO1, TPMT, and PGP were upregulated in OC tissues than in control. Moreover, DGKD and IDO1 were significantly associated with the human immune system. CONCLUSION:The differently expressed metabolism-related genes were identified to be a risk model in the prediction of the prognosis of OC. The identified hub genes related to OC prognosis may play important roles in influencing both human metabolism and the immune system.
10.3389/fcell.2021.690542
ACSM3 suppresses the pathogenesis of high-grade serous ovarian carcinoma via promoting AMPK activity.
Cellular oncology (Dordrecht)
PURPOSE:Ovarian carcinoma is the fifth commonest malignancy in females and exhibits a high recurrence rate. High-grade serous ovarian carcinoma (HGSOC) is the main histologic subtype. It displays extensive genetic heterogeneity. Here, we aimed to identify potential therapeutic targets for HGSOC. METHODS:Both bioinformatic data from TCGA and 73 pairs of tumor and normal samples from patients were analyzed to reveal the expression level of ACSM3 in HGSOC. Next, cellular and animal experiments, including cell proliferation, colony formation and xenograft assays were performed to explore the suppressive function of ACSM3. Finally, biochemical methods, AMP/ATP ratio measurements and Western blotting were used to elucidate the mechanism underlying the ACSM3-AMPK axis in HGSOC. RESULTS:After analyzing transcriptome data of TCGA HGSOC samples, we found that ACSM3 is down-regulated in patient samples compared with normal controls. This observation was validated using data from primary clinical samples. Proliferation, soft agar colony formation and xenograft assays revealed that ACSM3 is able to suppress HGSOC tumor growth both in vitro and in vivo. Moreover, we found that ACSM3 overexpression increased the AMP/ATP ratio and the phosphorylation level of AMPK at threonine 172. In addition, we found that AMPK silencing in EFO21 and SKOV3 cells completely abolished the anti-oncogenic effect of ACSM3. CONCLUSION:Our data indicate that the ACSM3-AMPK axis is involved in the pathogenesis of HGSOC and, as such, may act as a therapeutic target for this cancer.
10.1007/s13402-021-00658-1
THRSP identified as a potential hepatocellular carcinoma marker by integrated bioinformatics analysis and experimental validation.
Aging
Hepatocellular carcinoma (HCC) is the most common malignant liver tumor with high mortality and poor prognosis worldwide. This study aimed to identify hub genes and investigate the underlying molecular mechanisms in HCC progression by integrated bioinformatics analysis and experimental validation. Based on the Gene Expression Omnibus (GEO) databases and The Cancer Genome Atlas (TCGA), 12 critical differential co-expression genes were identified between tumor and normal tissues. Via survival analysis, we found higher expression of LCAT, ACSM3, IGF1, SRD5A2, THRSP and ACADS was associated with better prognoses in HCC patients. Among which, THRSP was selected for the next investigations. We found that THRSP mRNA expression was negatively correlated with its methylation and closely associated with clinical characteristics in HCC patients. Moreover, THRSP expression had a negative correlation with the infiltration levels of several immune cells (e.g., B cells and CD4+ T cells). qRT-PCR verified that THRSP was lower expressed in HCC tissues and cell lines compared with control. Silencing of THRSP promoted the migration, invasion, proliferation, and inhibited cell apoptosis of HCCLM and Huh7 cell lines. Decreased expression of THRSP promoted HCC progression by NF-κB, ERK1/2, and p38 MAPK signaling pathways. In conclusion, THRSP might serve as a novel biomarker and therapeutic target of HCC.
10.18632/aging.203900
KLF10 upregulates ACSM3 via the PI3K/Akt signaling pathway to inhibit the malignant progression of melanoma.
Oncology letters
Malignant melanoma is a type of skin cancer caused by mutations in the DNA of melanocytes. Melanoma is relatively rare compared with other types of skin tumors, but has a highly aggressive biological behavior and consequently, a poorer prognosis. Therefore, the present study aimed to explore the role and mechanism of Kruppel-like factor 10 (KLF10) and acyl-CoA medium-chain synthetase 3 (ACSM3) in melanoma progression. KLF10 expression in melanoma tissues was predicted using Gene Expression Profiling Interactive Analysis (GEPIA). KLF10 expression in healthy and melanoma cells was also detected using reverse transcription-quantitative PCR and western blotting. Cell transfection was performed to overexpress KLF10 or silence ACSM3. Cell viability, proliferation, migration, invasion and apoptosis were detected using Cell Counting Kit-8, colony formation, wound healing, Transwell and TUNEL assays, respectively. The activity of the ACSM3 promoter was detected using a dual-luciferase reporter assay, and the relationship between KLF10 and ACSM3 was detected using the GEPIA database and chromatin immunoprecipitation (ChIP). The results demonstrated that KLF10 expression was significantly downregulated in melanoma cells, especially in A375 cells. Compared with the Ov-NC group, KLF10 overexpression significantly inhibited the proliferation, invasion and migration of melanoma cells and promoted their apoptosis. Similar to KLF10, ACSM3 was also downregulated in A375 cells compared with that in the HEM group, and the GEPIA database analysis and ChIP assay results demonstrated that KLF10 expression was positively associated with ACSM3 expression. Furthermore, silencing ACSM3 significantly reversed the effect of KLF10 overexpression on cell proliferation, invasion and migration, and ACSM3 knockdown increased the levels of phosphorylated (p)-PI3K and p-Akt compared with the levels in the Ov-KLF10 + sh-NC group. Overall, the present study suggested that KLF10 inhibited the proliferation, invasion and migration of melanoma cells by targeting ACSM3 via the PI3K/Akt signaling pathway.
10.3892/ol.2022.13295