DKC1 enhances angiogenesis by promoting HIF-1α transcription and facilitates metastasis in colorectal cancer

Hou, Pingfu; Shi, Pei-Cong; Jiang, Tao; Yin, Hang; Chu, Sufang; Shi, Meilin; Bai, Jing; Song, Jun

doi:10.1038/s41416-019-0695-z

Cited by 63 publications

(51 citation statements)

References 50 publications

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“…Dyskeratosis congenita 1 is dysregulated across several cancers. In colorectal cancer (CRC), DKC1 stimulates angiogenesis and metastasis by stimulating HIF-1α and VEGF expression 62 . In addition to VEGF, HIFs also modulate angiogenic growth factor levels, including platelet-derived growth factor B, stromal-derived factor-1, and placenta growth factor 55 .…”

Section: Role Of Hifs In Tumor Progressionmentioning

confidence: 99%

The crosstalk between HIFs and mitochondrial dysfunctions in cancer development

et al. 2021

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Mitochondria are essential cellular organelles that are involved in regulating cellular energy, metabolism, survival, and proliferation. To some extent, cancer is a genetic and metabolic disease that is closely associated with mitochondrial dysfunction. Hypoxia-inducible factors (HIFs), which are major molecules that respond to hypoxia, play important roles in cancer development by participating in multiple processes, such as metabolism, proliferation, and angiogenesis. The Warburg phenomenon reflects a pseudo-hypoxic state that activates HIF-1α. In addition, a product of the Warburg effect, lactate, also induces HIF-1α. However, Warburg proposed that aerobic glycolysis occurs due to a defect in mitochondria. Moreover, both HIFs and mitochondrial dysfunction can lead to complex reprogramming of energy metabolism, including reduced mitochondrial oxidative metabolism, increased glucose uptake, and enhanced anaerobic glycolysis. Thus, there may be a connection between HIFs and mitochondrial dysfunction. In this review, we systematically discuss the crosstalk between HIFs and mitochondrial dysfunctions in cancer development. Above all, the stability and activity of HIFs are closely influenced by mitochondrial dysfunction related to tricarboxylic acid cycle, electron transport chain components, mitochondrial respiration, and mitochondrial-related proteins. Furthermore, activation of HIFs can lead to mitochondrial dysfunction by affecting multiple mitochondrial functions, including mitochondrial oxidative capacity, biogenesis, apoptosis, fission, and autophagy. In general, the regulation of tumorigenesis and development by HIFs and mitochondrial dysfunction are part of an extensive and cooperative network.

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Section: Role Of Hifs In Tumor Progressionmentioning

confidence: 99%

The crosstalk between HIFs and mitochondrial dysfunctions in cancer development

et al. 2021

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“…These genes were distributed in multiple pathways ( Figure S1A, Supporting Information), and some of them, such as MET [19] (ranked 1st), PRKDC [20] (ranked 8th), EXO1 [21] (ranked 14th), and TM4SF1 [22] (ranked 25th), have been reported to promote tumor cell proliferation ( Figure 1C). Among the top nine genes (Table S1, Supporting Information), five genes have been reported to affect CRC progression (MET, [19] DKC1, [23] GRHL3, [24] PRKDC, [20] and GPC4 [25] ). We individually silenced the remaining four genes (WER75, FAIM, GCSH, and TEX10) with two independent synthesized small interfering RNAs (siR-NAs) in HT29 cells ( Figure S1B, Supporting Information) and we found that the knockdown of TEX10, which ranked 7th in the aberrant expression analysis and was identified as an essential gene in the shRNA library screening (Table S1, Supporting Information), had the highest inhibitory efficacy on the growth of HT29 cells ( Figure S1C, Supporting Information).…”

Section: Screening Indicates That Tex10 Is Upregulated and Is Associamentioning

confidence: 99%

RNAi Screening Identifies that TEX10 Promotes the Proliferation of Colorectal Cancer Cells by Increasing NF‐κB Activation

et al. 2020

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Colorectal cancer (CRC) has become a predominant cancer worldwide. To understand the process of carcinogenesis, a short hairpin RNA library screening is employed to search for candidate genes that promote proliferation in the CRC cell line HT29. The candidate genes overlap with differentially expressed genes in 32 CRC tumor tissues in the GEO dataset GSE8671. The seventh‐ranked testis expressed 10 (TEX10) is upregulated in CRC and its knockdown decreases cell proliferation. The TEX10 high‐expression group exhibits worse overall survival (P = 0.003) and progression‐free survival (P = 0.001) than the TEX10 low‐expression group. TEX10 depletion decreases the growth of CRC cells in vitro and in vivo. Gene set enrichment analysis indicates that the nuclear factor‐kappa B pathway is significantly enriched in the genes downregulated by TEX10 knockdown. Mechanistically, TEX10 interacts with RELA and increases its nuclear localization. TEX10 promotes RELA occupancy at gene promoters and regulates the expression of a subset of RELA‐targeted genes, including TNFAIP8, SAT1, and IL6ST. Taken together, this study identifies that TEX10 promotes the proliferation of CRC cells in an RELA‐dependent manner. In addition, high TEX10 expression is associated with poor prognosis in CRC patients.

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“…BOP1 is a direct transcription target of β-catenin/TCF4, which induced cell migration and experimental metastasis of CRC cells ( Qi et al, 2016 ). DKC1 may regulate CRC angiogenesis and metastasis by directly activating HIF-1α transcription ( Hou et al, 2020 ). Ji et al (2019) showed that PTBP2 could elevate translational levels of RUNX2, which plays a vital role in CRC metastasis.…”

Section: Discussionmentioning

confidence: 99%

Construction and validation of an RNA-binding protein-associated prognostic model for colorectal cancer

Miao

Zhang²,

Su³

et al. 2021

PeerJ

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Colorectal cancer (CRC) is one of the most prevalent and fatal malignancies, and novel biomarkers for the diagnosis and prognosis of CRC must be identified. RNA-binding proteins (RBPs) are essential modulators of transcription and translation. They are frequently dysregulated in various cancers and are related to tumorigenesis and development. The mechanisms by which RBPs regulate CRC progression are poorly understood and no clinical prognostic model using RBPs has been reported in CRC. We sought to identify the hub prognosis-related RBPs and to construct a prognostic model for clinical use. mRNA sequencing and clinical data for CRC were obtained from The Cancer Genome Atlas database (TCGA). Gene expression profiles were analyzed to identify differentially expressed RBPs using R and Perl software. Hub RBPs were filtered out using univariate Cox and multivariate Cox regression analysis. We used functional enrichment analysis, including Gene Ontology and Gene Set Enrichment Analysis, to perform the function and mechanisms of the identified RBPs. The nomogram predicted overall survival (OS). Calibration curves were used to evaluate the consistency between the predicted and actual survival rate, the consistency index (c-index) was calculated, and the prognostic effect of the model was evaluated. Finally, we identified 178 differently expressed RBPs, including 121 up-regulated and 57 down-regulated proteins. Our prognostic model was based on nine RBPs (PNLDC1, RRS1, HEXIM1, PPARGC1A, PPARGC1B, BRCA1, CELF4, AEN and NOVA1). Survival analysis showed that patients in the high-risk subgroup had a worse OS than those in the low-risk subgroup. The area under the curve value of the receiver operating characteristic curve of the prognostic model is 0.712 in the TCGA cohort and 0.638 in the GEO cohort. These results show that the model has a moderate diagnostic ability. The c-index of the nomogram is 0.77 in the TCGA cohort and 0.73 in the GEO cohort. We showed that the risk score is an independent prognostic biomarker and that some RBPs may be potential biomarkers for the diagnosis and prognosis of CRC.

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DKC1 enhances angiogenesis by promoting HIF-1α transcription and facilitates metastasis in colorectal cancer

Cited by 63 publications

References 50 publications

The crosstalk between HIFs and mitochondrial dysfunctions in cancer development

The crosstalk between HIFs and mitochondrial dysfunctions in cancer development

RNAi Screening Identifies that TEX10 Promotes the Proliferation of Colorectal Cancer Cells by Increasing NF‐κB Activation

Construction and validation of an RNA-binding protein-associated prognostic model for colorectal cancer

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