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The aberrant inclusion of BOLA3 exon 3 promoted by HNRNPC acts as an oncogenic driver in esophageal squamous cell carcinoma [shHNRNPC RNA-seq]

ABSTRACT: Aberrant RNA splicing events produce transcripts to facilitate ESCC progression, yet how this splicing process is abnomally regulated remains elusive. Here, we unveil a alternative splicing axis of BOLA3 transcripts and its regulator HNRNPC in ESCC.The long isoform of BOLA3 (-L) with exon3 is highly expressed in ESCC and associated with poor prognosis. Functional assays demonstrate the pro-tumorigenic function of BOLA3-L in ESCC cells. HNRNPC binds to BOLA3-L pre-mRNA and promotes exon3 inclusion forming BOLA3-L. HNRNPC knockdown suppresses the tumorigenesis of ESCC cells, phenocopying BOLA3-L knockdown, which is significantly rescued by BOLA3-L overexpression. High expression of HNRNPC is correlated with the exon-3 inclusion of BOLA3 in ESCC and associated with poor prognosis. BOLA3-L maintains mitochondrial structural and functional stability, exerting pro-oncogenic effects through the WNT/β-catenin pathway. E2F7 acts as a key transcription factor to regulate the transcriptional upregulation of HNRNPC and promotes the inclusion of BOLA3 exon3.Taken together, our findings provide insights into how alternative splicing contributes to ESCC progression, by investgating a HNRNPC-BOLA3 splicing axis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235536 | GEO | 2024/01/01

REPOSITORIES: GEO

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The aberrant inclusion of BOLA3 exon 3 promoted by HNRNPC acts as an oncogenic driver in esophageal squamous cell carcinoma [11pairs RNA-seq]

Project description:Aberrant RNA splicing events produce transcripts to facilitate ESCC progression, yet how this splicing process is abnomally regulated remains elusive. Here, we unveil a alternative splicing axis of BOLA3 transcripts and its regulator HNRNPC in ESCC.The long isoform of BOLA3 (-L) with exon3 is highly expressed in ESCC and associated with poor prognosis. Functional assays demonstrate the pro-tumorigenic function of BOLA3-L in ESCC cells. HNRNPC binds to BOLA3-L pre-mRNA and promotes exon3 inclusion forming BOLA3-L. HNRNPC knockdown suppresses the tumorigenesis of ESCC cells, phenocopying BOLA3-L knockdown, which is significantly rescued by BOLA3-L overexpression. High expression of HNRNPC is correlated with the exon-3 inclusion of BOLA3 in ESCC and associated with poor prognosis. BOLA3-L maintains mitochondrial structural and functional stability, exerting pro-oncogenic effects through the WNT/β-catenin pathway. E2F7 acts as a key transcription factor to regulate the transcriptional upregulation of HNRNPC and promotes the inclusion of BOLA3 exon3.Taken together, our findings provide insights into how alternative splicing contributes to ESCC progression, by investgating a HNRNPC-BOLA3 splicing axis.

2024-01-01 | GSE235537 | GEO

The aberrant inclusion of BOLA3 exon 3 promoted by HNRNPC acts as an oncogenic driver in esophageal squamous cell carcinoma [shBOLA3-L RNA-seq]

2024-01-01 | GSE235535 | GEO

Transcriptome profiling of cells depleted of hnRNPC, Upf1, or co-depleted of hnRNPC and Upf1.

Project description:The purpose of this experiment was to compare differences in Alu-exon inclusion in cells depleted of hnRNPC, Upf1, or both.

2016-04-01 | E-MTAB-4008 | biostudies-arrayexpress

The m6A reader HNRNPC promotes non-small cell lung cancer progression by enhancing E2F2 mRNA stability

Project description:HNRNPC, as one of the m6A reading proteins, has been confirmed to be highly expressed in a variety of tumors and promote the occurrence and progression of tumors. Previous studies have confirmed that HNRNPC significantly promoted the proliferation, migration and invasion of NSCLC cells, and its high expression was related to the clinical stage, lymph node and distant metastasis of patients, and could be used as an indicator of poor prognosis of NSCLC. However, the role of HNRNPC in regulating gene expression through m6A methylation modification in the occurance and progression of NSCLC remains largely unexplored. To investigate the target genes bound by HNRNPC, samples from A549 cells were harvested by RIP lysis buffer, and then the lysates were immunoprecipitated by 5μg anti-HNRNPC antibody. finally, the potential target genes were identified by RIP-seq.

2023-12-05 | GSE249094 | GEO

hNRNPC iCLIP

Project description:hNRNPC iCLIP

| PRJEB2253 | ENA

Function of HNRNPC in breast cancer cells by controlling the dsRNA-induced interferon response

Project description:Elevated expression of RNA binding protein HNRNPC has been reported in cancer cells, while the essentialness and functions of HNRNPC in tumors were not clear. We showed that repression of HNRNPC in the breast cancer cells MCF7 and T47D inhibited cell proliferation and tumor growth. Our computational inference of the key pathways and extensive experimental investigations revealed that the cascade of interferon responses mediated by RIG-I was responsible for such tumor-inhibitory effect. Interestingly, repression of HNRNPC resulted in accumulation of endogenous double-stranded RNA (dsRNA), the binding ligand of RIG-I. These up-regulated dsRNA species were highly enriched by Alu sequences and mostly originated from pre-mRNA introns that harbor the known HNRNPC binding sites. Such source of dsRNA is different than the recently well-characterized endogenous retroviruses that encode dsRNA. In summary, essentialness of HNRNPC in the breast cancer cells was attributed to its function in controlling the endogenous dsRNA and the down-stream interferon response. This is a novel extension from the previous understandings about HNRNPC in binding with introns and regulating RNA splicing.

2018-08-23 | GSE100451 | GEO

Differentially expressed genes in HNRNPC knockdown MHCC97H cells

Project description:HNRNPC plays an important role in HCC metastasis, HNRNPC knockdown by specific shRNA (HNRNPC-shRNA) significantly inhibited the migration and invasion of MHCC97H cells, while HNRNPC overexpression exerted the opposite effect. To elucidate the mechanisms by which HNRNPC facilitated HCC metastasis, we performed microarray analysis to compare the transcription profiling between the MHCC97H-shcontrol and MHCC97H-shHNRNPC cells.

2022-07-27 | GSE180789 | GEO

lncRNA CYTOR promotes aberrant glycolysis and mitochondrial respiration via HNRNPC-mediated ZEB1 stabilization in oral squamous cell carcinoma

Project description:Oral squamous cell carcinoma (OSCC), the most common malignancy of the oral and maxillofacial region, severely affects human health. However, current treatments for OSCC commonly show only a ~60% five-year survival rate of patients with distant metastases, indicating an urgent need for targeted treatments for patients with advanced metastases. Here, we report a survival-related long non-coding RNA, CYTOR, which is highly expressed in the lesions of oral cancer patients. We found that CYTOR can promote both migration and invasion in oral cancer cells as well as the epithelial-mesenchymal transition (EMT). RNA-sequencing of CYTOR-knockdown oral cancer cells revealed that CYTOR can regulate mitochondrial respiration and RNA splicing. Mechanistically, we found that nuclear-localized CYTOR interacts with HNRNPC, resulting in stabilization of ZEB1 mRNAs by inhibiting the nondegradative ubiquitination of HNRNPC. By synthesizing CYTOR-targeting small interfering RNAs (siRNAs) encapsulated in Nanoscale Metal Organic Frameworks (NMOFs), we demonstrate the targeted suppression of CYTOR to inhibit invasion and metastasis of oral cancer cells in a nude mouse model. Cumulatively, this study reveals the potential role of the CYTOR-HNRNPC-ZEB1 axis in regulating mitochondrial metabolism and glycolysis of oral cancer cells, and illustrates the effective use of lncRNA targeting in anti-metastatic cancer therapies.

2022-01-09 | GSE193143 | GEO

The spliceosome factor USP39 promotes hepatocellular carcinoma malignancy through regulating mRNA splicing

Project description:Abnormal alternative splicing (AS) caused by alterations to splicing factors contributes to tumor progression. Nonetheless, the relevant targets and mechanisms remain elusive in hepatocellular carcinoma (HCC). Here, we reported that overexpression of Ubiquitin-specific protease 39 (USP39), a spliceosome component of the U4/U6.U5 tri-snRNP complex, is associated with poor clinical outcomes and proliferative signaling. Functionally, hepatocyte-specific USP39 knockin mice exhibited enhanced hepatocarcinogenesis. In vitro, USP39 promoted HCC cell proliferation and cell cycle progression in a spliceosome-dependent manner. Transcriptomic analysis revealed that USP39 depletion led to comprehensively impaired constitutive splicing and intriguingly, selective AS of hundreds of genes. USP39-mediated splicing switch of KANK2-S to KANK2-L increased the tumorigenic potential of HCC cells through accelerating KANK2 translation. Mechanistically, USP39 modulates exon inclusion/exclusion via interaction with SRSF6 or hnRNPC in a position-dependent manner. These findings highlight a role for USP39 as a splicing regulator in HCC biology and establishing its position-dependent splicing model.

2023-10-24 | PXD035928 | Pride

The role of HNRNPC-PABPC4 on polyA site selection

Project description:Cancer cells often co-opt post-transcriptional regulatory mechanisms to achieve pathologic expression of gene networks that drive metastasis. Translational control is a major regulatory hub in oncogenesis, however its effects on cancer progression remain poorly understood. To address this, we used ribosome profiling to compare genome-wide translation efficiencies of poorly and highly metastatic breast cancer cells and patient-derived xenografts. We developed novel regression-based methods to analyze ribosome profiling and alternative polyadenylation data, and identified HNRNPC as a translational controller of a specific mRNA regulon. Mechanistically, HNRNPC, in concert with PABPC4, binds near to poly(A) signals, thereby governing the alternative polyadenylation of a set of mRNAs. We found that HNRNPC and PABPC4 are downregulated in highly metastatic cells, which causes HNRNPC-bound mRNAs to undergo 3’ UTR lengthening and subsequently, translational repression. We showed that modulating HNRNPC expression impacts the metastatic capacity of breast cancer cells in xenograft mouse models. We also found that a small molecule, previously shown to induce a distal-to-proximal poly(A) site switching, counteracts the HNRNPC-PABPC4 driven deregulation of alternative polyadenylation and decreases the metastatic lung colonization by breast cancer cells in vivo.

2023-02-20 | GSE186638 | GEO

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