Dual Regulatory Mechanisms of Expression and Mutation Involving Metabolism-Related Genes FDFT1 and UQCR5 during CLM

Ma, Yu‐Shui; Wu, Zhijun; Zhang, Hongwei; Cai, Bo; Huang, Tao; Long, Hui-Deng; Xu, Hong; Zhao, Yang; Yin, Yuzhen; Xue, Sheng; Li, Liu; Liu, Cheng‐Lin; Xie, Ruting; Liu, Ji‐Bin; Wu, Xuming; Fu, Da

doi:10.1016/j.omto.2019.04.008

Cited by 18 publications

(18 citation statements)

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“…A study showed that downregulation of FDFT1 was correlated with malignant progression and poor prognosis in colorectal cancer. Somatic variants revealed FDFT1 that frequently mutated only in the liver metastatic patients and targeting FDFT1 could be a feasible strategy in colon cancer, especially in the colorectal liver metastatic patients ( 31 ). To sum up, the genes in our model played important roles in colon cancer and were worthy for further studies.…”

Section: Discussionmentioning

confidence: 99%

A Novel Ferroptosis Related Gene Signature for Prognosis Prediction in Patients With Colon Cancer

Nie

Shan

et al. 2021

Front. Oncol.

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PurposeColon cancer (CC) is a serious disease burden. The prognosis of patients with CC is different, so looking for effective biomarkers to predict prognosis is vitally important. Ferroptosis is a promising therapeutic and diagnosis strategy in CC. However, the role of ferroptosis in prognosis of CC has not been studied. The aim of the study is to build a prognosis model related ferroptosis, and provide clues for further therapy of CC.MethodsThe RNA-seq data were from TCGA (training group) and GEO (testing group). The R language and Perl language were used to process and analyze data. LASSO regression analysis was used to build the prognosis model. ssGSEA was used to compare the immune status between two groups. Immunohistochemistry was used to detect expression of AKR1C1 and CARS1 in colon cancer tissues and adjacent tissues.ResultsThe prognosis model consisted of five ferroptosis related genes (AKR1C1, ALOX12, FDFT1, ATP5MC3, and CARS1). The area under curve (AUC) at 1-, 2-, and 3-year were 0.668, 0.678, and 0.686, respectively. The high- and low-risk patients had significant survival probability and could be clearly distinguished by the PCA and t-SNE analysis. The multivariate cox regression analysis also showed the riskscore is an independent prognosis factor. Importantly, we found that the immune status between high- and low-risk patients were different obviously, such as CD8+T cells. And STING, a new promising immune target, was also correlated to our signature genes statistically significantly.ConclusionOur ferroptosis prognosis signature could predict survival of CC patients to a certain degree. And the crosstalk between ferroptosis and immune, especially STING need further studies.

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Section: Discussionmentioning

confidence: 99%

A Novel Ferroptosis Related Gene Signature for Prognosis Prediction in Patients With Colon Cancer

Nie

Shan

et al. 2021

Front. Oncol.

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“…Furthermore, increasing cellular cholesterol can drive intestinal stem cell proliferation and tumorigenesis through the activation of nuclear SREBP-2 ( 128 ). Also, SQS is frequently mutated and dysregulated in the liver metastatic cohort of colorectal cancer ( 129 ). The final enzyme of the cholesterol pathway, DHCR24, is significantly elevated and associated with advanced clinical stage and overall survival in bladder and endometrial cancer, which is mediated by several oncogenesis-associated biological processes ( 130 , 131 ).…”

Section: Srebp-2 Signaling and The Enzymes From The Mevalonate Pathwamentioning

confidence: 99%

“…Associated with increasing Gleason score and poor survival through modulation of small GTPase/Akt axis(103,104) SQSThe allele at rs2645429 is significantly associated with cancer risk and aggressive phenotypes(105) Breast cancer SREBP-2 CtBP can form a complex with ZEB1 to transcriptionally repress SREBP-2 expression and activate TGF-β signaling(106) SREBP-2, HMGCR, FPPS, SQS, DHCR7TP53 mutation upregulates with the mevalonate pathway genes, HMGCR, FPPS, SQS, and DHCR7 through interaction with SREBP-2 (20)SREBPsPI3K or K-Ras can induce mTORC1 signaling to promote cancer growth through SREBP-2 or SREBP-1 activation (107) SREBP-2 Highly expressed in cancer tissues and correlated with a poor prognosis (15) SREBP-2 Increased during the early stages of osteoclast formation under the control of the RANKL/cAMP-CREB signaling and induced the expressions of NFATc1 and matrix metalloproteinases for cancer-induced osteolysis (15) HMGCR Correlated with the cancer risk and poor survival (111-113) Cholesterol Implicated as a cancer, tumor growth and metastasis risk factor (114) 27-hydroxycholesterol Increases the proliferation of estrogen receptor (ER)-positive breast cancer through the activation of ER and LXR (115) Lung cancer HMGCR The allele at rs12916 is significantly associated with the attained age for cancer patients (111) SQS The allele at rs2645429 is a risk factor for non-small cell lung cancer (NSCLC) (116) SQS Associated with the metastasis and poor prognosis by regulating NF-κB-mediated the up-regulation of matrix metallopeptidase-1 or extracellular signal-regulated kinase signaling (117, 120) FPPS Promotes cell invasion and epithelial mesenchymal transition (EMT) through the RhoA/ROCK1 pathway (118) GGPPSS Increases cancer invasion and migration by regulating EMT (119) Hepatocellular carcinoma SREBP-2 p53 induces the accumulation and stabilization of mature SREBP-2 by transcriptional ABCA1 induction (21) SREBP-2 ASPP2, a p53 activator interacts with SREBP-2 in the nucleus to negatively affect the mevalonate pathway (122) SREBP-2 Staphylococcal nuclease and tudor domain containing-1 (SND-1) results in the accumulation of cholesteryl esters through the activation of SREBP-2 (123) SREBP-2 Binds to specific sites in SND-1 promoter to contribute lipid metabolism reprogramming (91) SREBP-2, HMGCR Fatty acid synthase ablation promotes nuclear localization of SREBP-2 and increases HMGCR expression to maintain carcinogenesis (124) SREBP-2, HMGCR Forkhead Box M1 has a positive correlation with SREBP-2 or HMGCR in hepatocellular carcinoma through protein geranylgeranylation Promotes cell growth, migration and colony formation through interaction with c-Myc; SREBP-2 is upregulated in clinical samples host gene 16 directly regulates the miR-195/SREBP-2 axis to promote cancer progression (drives intestinal stem cell proliferation and tumorigenesis through SREBP-2 expression (128)SQSFrequently mutated and dysregulated in liver metastasis(129) Bladder and endometrial cancerDHCR24Significantly elevated and associated with advanced clinical stage and overall survival(130,131) …”

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confidence: 99%

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

Xue

Zhang

et al. 2020

Front. Oncol.

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Recently, targeting metabolic reprogramming has emerged as a potential therapeutic approach for fighting cancer. Sterol regulatory element binding protein-2 (SREBP-2), a basic helix-loop-helix leucine zipper transcription factor, mainly regulates genes involved in cholesterol biosynthesis and homeostasis. SREBP-2 binds to the sterol regulatory elements (SREs) in the promoters of its target genes and activates the transcription of mevalonate pathway genes, such as HMG-CoA reductase (HMGCR), mevalonate kinase and other key enzymes. In this review, we first summarized the structure of SREBP-2 and its activation and regulation by multiple signaling pathways. We then found that SREBP-2 and its regulated enzymes, including HMGCR, FPPS, SQS, and DHCR4 from the mevalonate pathway, participate in the progression of various cancers, including prostate, breast, lung, and hepatocellular cancer, as potential targets. Importantly, preclinical and clinical research demonstrated that fatostatin, statins, and N-BPs targeting SREBP-2, HMGCR, and FPPS, respectively, alone or in combination with other drugs, have been used for the treatment of different cancers. This review summarizes new insights into the critical role of the SREBP-2-regulated mevalonate pathway for cancer and its potential for targeted cancer therapy.

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“…Recent advances in high-throughput next-generation sequencing (NGS) technologies enable the complete sequencing of entire genomes and allow us to analyze a number of cancer genome profiles. 14 , 15 , 16 , 17 Recently, fibroblast growth factor receptor 2 (FGFR2) kinase fusion was found to occur in 13.6% of intrahepatic CHOL by parallel whole-transcriptome sequencing in eight specimens. 18 Competing endogenous RNAs (ceRNAs), natural decoys that compete for a common pool of microRNAs (miRNA, miR), represent a novel layer of gene regulation by systematically functionalizing miRNA response element (MRE)-harboring non-coding RNAs, such as long non-coding RNAs (lncRNAs), pseudogenes, and circular RNAs (circRNAs), and forming complex miRNA-mediated ceRNA networks.…”

Section: Introductionmentioning

confidence: 99%

Whole-Transcriptome Sequencing Identifies Key Differentially Expressed mRNAs, miRNAs, lncRNAs, and circRNAs Associated with CHOL

Chu

Jiang

et al. 2020

Molecular Therapy - Nucleic Acids

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To systematically evaluate the whole-transcriptome sequencing data of cholangiocarcinoma (CHOL) to gain more insights into the transcriptomic landscape and molecular mechanism of this cancer, we performed whole-transcriptome sequencing based on the tumorous (C) and their corresponding non-tumorous adjacent to the tumors (CP) from eight CHOL patients. Subsequently, differential expression analysis was performed on the C and CP groups, followed by functional interaction prediction analysis to investigate gene-regulatory circuits in CHOL. In addition, The Cancer Genome Atlas (TCGA) for CHOL data was used to validate the results. In total, 2,895 differentially expressed messenger RNAs (dif-mRNAs), 56 differentially expressed microRNAs (dif-miRNAs), 151 differentially expressed long non-coding RNAs (dif-lncRNAs), and 110 differentially expressed circular RNAs (dif-circRNAs) were found in CHOL samples compared with controls. Enrichment analysis on those differentially expressed genes (DEGs) related to miRNA, lncRNA, and circRNA also identified the function of spliceosome. The downregulated hsa-miR-144-3p were significantly enriched in the competing endogenous RNA (ceRNA) complex network, which also included 7 upregulated and 13 downregulated circRNAs, 7 upregulated lncRNAs, and 90 upregulated and 40 downregulated mRNAs. Moreover, most of the DEGs and a few of the miRNAs (such as hsa-miR-144-3p) were successfully validated by TCGA data. The genes involved in RNA splicing and protein degradation processes and miR-144-3p may play fundamental roles in the pathogenesis of CHOL.

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Dual Regulatory Mechanisms of Expression and Mutation Involving Metabolism-Related Genes FDFT1 and UQCR5 during CLM

Cited by 18 publications

References 48 publications

A Novel Ferroptosis Related Gene Signature for Prognosis Prediction in Patients With Colon Cancer

A Novel Ferroptosis Related Gene Signature for Prognosis Prediction in Patients With Colon Cancer

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

Whole-Transcriptome Sequencing Identifies Key Differentially Expressed mRNAs, miRNAs, lncRNAs, and circRNAs Associated with CHOL

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