DHX32 Promotes Angiogenesis in Colorectal Cancer Through Augmenting β-catenin Signaling to Induce Expression of VEGFA

Lin, Hongxin; Fang, Zanxi; Su, Yuanhui; Li, Peihua; Wang, Jingkun; Liao, Hongfeng; Hu, Qing; Chunlei, Ye; Fang, Yizhen; Luo, Qin; Lin, Zhiyuan; Pan, Chao; Wang, Fen; Zhang, Zhongying

doi:10.1016/j.ebiom.2017.03.012

Cited by 18 publications

(13 citation statements)

References 35 publications

(48 reference statements)

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“…DHX32 is an RNA helicase and belongs to DEAD/Hbox family of proteins. It is up-regulated in colorectal cancer and is known to induce expression of Vascular Endothelial Growth Factor A (VEGFA) in a β-catenin dependent mechanism, contributing to angiogenesis, which is a hypoxia dependent process (Lin et al 2017).…”

Section: Correlation Between Intragenic Dna Methylation and Exon Expression Levelmentioning

confidence: 99%

Hypoxia-induced changes in intragenic DNA methylation correlate with alternative splicing in breast cancer

et al. 2020

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The tumor microenvironment is marked by gradients in the level of oxygen and nutrients, with oxygen levels reaching a minimum at the core of the tumor, a condition known as tumor hypoxia. Mediated by members of the HIF family of transcription factors, hypoxia leads to a more aggressive tumor phenotype by transactivation of several genes as well as reprogramming of pre-mRNA splicing. Intragenic DNA methylation, which is known to affect alternative splicing in cancer, could be one of several reasons behind the changes in splicing patterns under hypoxia.Here, we have tried to establish a correlation between intragenic DNA methylation and alternative usage of exons in tumor hypoxia. First, we have generated a custom hypoxia signature consisting of 34 genes that are up-regulated under hypoxia and are direct targets of HIF-1α. Using this gene expression signature, we have successfully stratified publicly available breast cancer patient samples into hypoxia positive and hypoxia negative groups followed by mining of differentially spliced isoforms between these groups. The Hypoxia Hallmark signature from MSigDB was also used independently to stratify the same tumor samples into hypoxic and normoxic. We found that 821 genes were showing differential splicing between samples stratified using a custom signature, whereas, 911 genes were showing differential splicing between samples stratified using the MSigDB signature. Finally, we performed multiple correlation tests between the methylation levels (α) of microarray probes located within 1 kilo base pairs of isoform-specific exons using those exons' expression levels in the same patient samples in which the methylation level was recorded. We found that the expression level of one of the exons of DHX32 and BICD2 significantly correlated with the methylation levels, and we were also able to predict patient survival (p-value: 0.02 for DHX32 and 0.0024 for BICD2). Our findings provide new insights into the potential functional role of intragenic DNA methylation in modulating alternative splicing during hypoxia.

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Section: Correlation Between Intragenic Dna Methylation and Exon Expression Levelmentioning

confidence: 99%

Hypoxia-induced changes in intragenic DNA methylation correlate with alternative splicing in breast cancer

et al. 2020

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“…DHX32 upregulation inhibited β-catenin ubiquitination, prolonged the half-life of β-catenin and improved the stability of β-catenin, thus promoting VEGFA expression. DHX32 knockdown significantly inhibited colorectal cancer xenograft growth and angiogenesis in nude mice (54). The results indicated that DHX32 induces VEGFA expression by augmenting β-catenin signaling, thereby promoting angiogenesis in colorectal cancer (Fig.…”

Section: Dhx32 and Cancermentioning

confidence: 79%

Structure and function of DEAH-box helicase 32 and its role in cancer (Review)

et al. 2021

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DEAH-box helicase 32 (DHX32) is an RNA helicase with unique structural characteristics that is involved in numerous biological processes associated with RNA, including ribosome biosynthesis, transcription, mRNA splicing and translation. Increasing evidence suggests that abnormal DHX32 expression contributes to cancer initiation and development, due to dysregulated cell proliferation, differentiation, apoptosis and other processes. In the current review, the discovery, structure and function of DHX32, as well as the association between abnormal DHX32 expression and tumors are discussed. DHX32 expression is downregulated in acute lymphoblastic leukemia, but upregulated in solid tumors, including colorectal and breast cancer. Furthermore, DHX32 expression levels are associated with the pathological and clinical features of the cancer. Therefore, DHX32 may serve as a novel liquid biopsy marker for auxiliary diagnosis and prognosis screening, as well as a possible target for cancer therapy. The molecular mechanism underlying the contribution of DHX32 towards the initiation and development of cancer requires further investigation for the development of anticancer treatments based on manipulating DHX32 expression and function.

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“…RT-PCR assay was performed with 2 × SYBR Green qPCR Master Mix (Bimake; Cat: B21202) in the LightCycler 480 Real-Time PCR System (Roche) in accordance with the manufactures’ protocol. The relative expression of targeted genes was calculated using 2 –ΔΔCt method [ 13 ] and was normalized to the expression of ACTB in HCC cells.…”

Section: Methodsmentioning

confidence: 99%

“…The expression of DHX32 was significantly related to clinically pathological features of colorectal cancer, and can be served as a prognostic biomarker for colorectal cancer patients [ 10 ]. It was reported that DHX32 overexpression promoted the proliferation and mobility of colorectal cancer cells and augmented β-catenin signaling to enhance angiogenesis in colorectal cancer [ 9 , 13 ]. Moreover, high level of DHX32 expression also predicted poor prognosis in breast cancer patients [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

DEAH-box polypeptide 32 promotes hepatocellular carcinoma progression via activating the β-catenin pathway

Yuan

et al. 2021

Annals of Medicine

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Purpose Hepatocellular carcinoma (HCC) is refractory cancer with high morbidity and high mortality. DEAH-box polypeptide 32 (DHX32) was upregulated in several types of malignancies and predicted poor prognosis. Herein, we investigated the role of DHX32 in HCC progression. Methods The expression of DHX32, β-catenin, and epithelial-mesenchymal transition (EMT)-related makers were determined by Western blot and quantitative real-time PCR assays. Cell proliferation was tested by EdU cell proliferation assay. The effect of DHX32 and β-catenin on cell migration and invasion were detected by wound-healing and Traswell invasion assays. Tumour xenografts were performed to determine the effect of DHX32 on HCC tumour growth. Results High level of DHX32 expression was associated with reduced overall survival in HCC patients. DHX32 expression was upregulated in human HCC cells and ectopic expression of DHX32 induced EMT, promoted the mobility and proliferation of HCC cells, and enhanced tumour growth in vivo . Silencing DHX32 reversed EMT, inhibited the malignancy behaviors of HCC cells, and suppressed tumour growth. Mechanistically, silencing DHX32 decreased the expression of β-cateninin in nucleus and β-catenin siRNA abrogated DHX32-mediated HCC progression. Conclusion DHX32 was an attractive regulator of HCC progression and indicated DHX32 canserve as a potential biomarker and therapeutic target for HCC patients.

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DHX32 Promotes Angiogenesis in Colorectal Cancer Through Augmenting β-catenin Signaling to Induce Expression of VEGFA

Cited by 18 publications

References 35 publications

Hypoxia-induced changes in intragenic DNA methylation correlate with alternative splicing in breast cancer

Hypoxia-induced changes in intragenic DNA methylation correlate with alternative splicing in breast cancer

Structure and function of DEAH-box helicase 32 and its role in cancer (Review)

DEAH-box polypeptide 32 promotes hepatocellular carcinoma progression via activating the β-catenin pathway

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