Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Splice switching of SULT1C2 mRNA to lncRNA elicits tumor progression and immune evasion through triggering cholesterol biosynthesis

ABSTRACT: Emerging evidence shows that protein-coding genes can produce noncoding splice forms in addition to their canonical mRNA transcripts. However, the coding-to-noncoding transformation of mRNA and its pathological significance in cancer remain poorly understood. Here, we explored the noncoding variants of protein-coding genes in hepatocellular carcinoma (HCC), and identified a novel sulfotransferase 1C2 (SULT1C2) noncoding variant, lncSULT1C2, as a driver of hepatic tumorigenesis. Polypyrimidine tract-binding protein 1 (PTBP1) mediates the splice switching of SULT1C2 pre-mRNA to lncSULT1C2. Increased lncSULT1C2 expression accelerated the tumorigenicity of HCC cells by reprogramming cholesterol biosynthesis. LncSULT1C2-induced cholesterol accumulation activated mTORC1 signaling and drove the PD-L1-mediated antitumor immune response. High lncSULT1C2 expression decreased the efficacy of anti-PD-1 immunotherapy in mice. GalNAc-conjugated antisense oligonucleotide (ASO) against lncSULT1C2 elicited robust antitumor effects. This study unravels lncSULT1C2 as a previously unrecognized oncogenic noncoding variant of SULT1C2 and highlight the relevance of lncSULT1C2 in cholesterol metabolism reprogramming and tumor immune evasion.

ORGANISM(S): Homo Sapiens

SUBMITTER: Xianghuo He

PROVIDER: PXD068724 | iProX | Tue Sep 23 00:00:00 BST 2025

REPOSITORIES: iProX

ACCESS DATA

Json Xml

Similar Datasets

RNA N6-methyladenosine methyltransferase METTL3 drives NAFLD-HCC and is a therapeutic target for boosting immunotherapy [m6A-seq]

Project description:Non-alcoholic fatty liver disease (NAFLD) is an emerging risk factor of hepatocellular carcinoma (HCC). However, the mechanism and target therapy on NAFLD-HCC are still unclear. Here, we identify that the N6-methyladenosine (m6A) methyltransferase METTL3 promotes NAFLD-HCC. Hepatocyte-specific Mettl3 knockin exacerbated NAFLD-HCC formation while Mettl3 knockout exerted an opposite effect in mice. Single-cell RNA-seq revealed that METTL3 suppressed antitumor immune response by reducing infiltration of Gzmb+ and IFN-γ+ CD8+ T-cell, thereby facilitating immune escape. Mechanistically, METTL3 mediates SCAP mRNA m6A to promote its translation, leading to the activation of cholesterol biosynthesis. This enhanced secretion of cholesterol and cholesteryl esters, lipotoxins that impaired CD8+ T cell function in tumor microenvironment. Targeting of METTL3 by sgRNA, nanoparticle-siRNA, or pharmacological inhibitor (STM2457) in combination with anti-PD1 synergized to reinvigorate cytotoxic CD8+ T cells and mediate tumor regression. Together, METTL3 is a therapeutic target in NAFLD-HCC, especially in conjunction with immune checkpoint blockade (ICB) therapy.

2023-08-23 | GSE233807 | GEO

RNA N6-methyladenosine methyltransferase METTL3 drives NAFLD-HCC and is a therapeutic target for boosting immunotherapy [RNA-Seq]

2023-08-23 | GSE233806 | GEO

Lactate promotes cholesterol uptake by facilitating SCARB1 expression through histone H3K18 lactylation

Project description:Metabolic reprogramming supports the proliferation of cancer cells under hypoxic stress, including enhanced glycolysis and altered fatty acid metabolism. However, the mechanism underlying its regulation of cholesterol metabolism remains incompletely understood. Here, we show that lactate-induced cholesterol accumulation activates mammalian target of rapamycin complex 1 (mTORC1) signaling under hypoxic conditions, thereby promoting hepatocellular carcinoma (HCC) progression. Mechanistically, lactate upregulates scavenger receptor class B type 1 (SCARB1) expression by enhancing histone H3 lysine 18 lactylation (H3K18la), leading to increased cholesterol levels. We furthermore demonstrate that SCARB1-mediated cholesterol uptake is essential for the activation of mTORC1, which promotes tumor growth by preventing HCC cells from excessive autophagy. Importantly, analysis of clinical HCC samples showed a positive correlation between H3K18la and SCARB1 expression. Taken together, these findings provide novel insights into hypoxia-driven metabolic reprogramming and reveal a previously unrecognized connection between lactate and cholesterol metabolism, suggesting a potential innovative cancer therapy for HCC.

2025-09-18 | GSE308360 | GEO

RNA-seq data for tumor and adjacent non-tumor tissues from hepatocellular carcinoma patients with anti-PD-1 therapy

Project description:Immune checkpoint inhibitors elicit durable antitumor effects in multiple cancers, yet not all patients respond. Here, we aimed to develop and validate a molecular classification of hepatocellular carcinoma (HCC) patients based on 42 fatty acid degradation genes and demonstrate its predictive ability in the clinical response of anti-PD1 therapy in HCC patients. We studied global mRNA expression profiles from 41 primary tumor tissues and 25 nontumor tissues derived from 41 HCC patients. 17 patients received anti-PD1 therapy and were available with clinical response. 63 samples were also sent for lipidomics analysis. Methods for the study included gene expression analysis, consensus clustering analysis, pathway enrichment analysis, and Single-Sample Gene Set Enrichment Analysis (ssGSEA). This study identified and validated a novel molecular classification based on fatty acid degradation that predicts clinical response to anti-PD-1 therapy in hepatocellular carcinoma.

2023-05-01 | GSE202069 | GEO

Dietary cholesterol promotes fatty liver-associated liver cancer by inducing aberrant genomic expression and mutations

Project description:We investigated the effects of cholesterol on nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) in diethylnitrosamine-injected mice fed high-fat high-cholesterol (HFHC) diet versus high-fat (HF) alone. mRNA microarray analysis was applied for expressional aberrations.

2018-09-27 | E-MTAB-6002 | biostudies-arrayexpress

Oleuropein reprograms the immunosuppressive footprint of tumor-associated myeloid cells and enhances PD-L1/PD-1 blockade immunotherapy in cancer

Project description:Therapies based on PD-1/PD-L1 blockade fail in most cancer patients. Here we evaluated the capacities of oleuropein to reprogram tumor-associated immunosuppressive myeloid cells to increase the potency of immunotherapies. Oleuropein caused major global reprogramming of monocytic and granulocytic myeloid-derived suppressor cells and tumor-associated macrophages towards immunostimulatory subsets. Differential quantitative proteomics uncovered activated and down-modulated pathways at high resolution for each subset which regulated major differentiation programs. Oleuropein significantly potentiated the capacities of myeloid cells to activate T-cells and enhanced antitumor properties of PD-1 blockade, either by systemic anti-PD-1 antibody administration, or locally by intratumor antibody delivery with a self-amplifying RNA vector based on Semliki Forest virus. Combination therapies decreased tumor infiltration by immunosuppressive myeloid cells and increased dendritic cell recruitment within draining lymph nodes, leading to systemic antitumor T-cell responses. Potent therapeutic activities were evident in lung cancer models resistant to immunotherapies and in colon cancer models.

2024-12-08 | PXD047616 | JPOST Repository

Rader HHDL and BioBank genotyping

Project description:The presence of a coding variant affecting plasma high density lipoprotein cholesterol (HDLC) levels was evaluated in subjects with elevated or normal plasma levels of HDLC. Carriers of the variant were further analyzed phenotypically

2017-06-21 | GSE100271 | GEO

Rader HHDL genotyping

Project description:The presence of a coding variant affecting plasma high density lipoprotein cholesterol (HDLC) levels was evaluated in subjects with elevated plasma levels of HDLC.

2015-12-17 | GSE76065 | GEO

RNA-seq of human liver cancer cell line SNU-398 treated with a novel sulfane sulfur donor (PSCP) against untreated controls

Project description:This study elucidates the molecular mechanisms underlying the antitumor effects of a novel sulfane sulfur donor compound on hepatocellular carcinoma (HCC) cells using RNA sequencing analysis. While sulfane sulfur has emerged as a crucial signaling molecule with therapeutic potential in cancer treatment, its precise mechanisms of action remain to be fully elucidated. We synthesized a novel sulfane sulfur donor (persulfided cysteine precursor, PSCP) that exhibits potent inhibitory effects on HCC cells. Through comprehensive RNA-seq analysis of PSCP-treated HCC cells versus controls, we uncovered a complex regulatory mechanism involving mitochondrial damage, AMPK activation, and p53-mediated cellular responses, including both proliferation inhibition and apoptosis induction. Our findings demonstrate that PSCP exerts its anti-HCC effects through a mitochondrial damage-AMPK-p53 signaling cascade, with p53 serving as a key mediator that both suppresses cell proliferation and promotes apoptosis. These results provide novel insights into the antitumor mechanisms of sulfane sulfur compounds and highlight their therapeutic potential in HCC treatment.  Treatment group: SNU398 HCC cells treated with 200 μM PSCP for 24 hours  Control group: SNU398 cells treated with vehicle control  Three-four biological replicates per group  mRNA extraction using TRIzol reagent (Invitrogen, MD, USA)  Sequencing performed by Biomarker Technologies (Guangzhou, China)  Sequencing platform: Oxford Nanopore Technologies (Oxford, UK)  Data analysis conducted using BMK_Cloud platform

2025-01-31 | E-MTAB-14578 | biostudies-arrayexpress

Epigenetic Reprogramming Modulates Malignant Properties of Human Liver Cancer Cells

Project description:Reversal of DNA hypermethylation and associated gene silencing is an emerging cancer therapy approach. In this context we have addressed the impact of epigenetic alterations and local microenvironment on the functional and transcriptional reprogramming of hepatic cancer stem cells. (CSCs) using the DNMT1 inhibitor Zebularine (ZEB). We show for the first time that cellular context is a critical determinant in the response to DNMT1 inhibition resulting in either a long term epigenetically driven malignant reprogramming or an effective antitumor therapeutic reprogramming. Furthermore, permanent reduction of DNMT1 protein level renders the HCC cell lines insensitive to both DNMT1 inhibition and cellular context. These results emphasize the importance of decoding the mechanisms involved in therapeutic application of DNA demethylating agents. Huh7 and PLC treated with ZEB, and Huh7 depleted for DNMT1

2014-05-26 | E-GEOD-47932 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data