Long non-coding RNA CCAL regulates colorectal cancer progression by activating Wnt/β-catenin signalling pathway via suppression of activator protein 2α

Ma, Yanlei; Yang, Yongzhi; Feng, Wenquan; Moyer, Mary Pat; Wei, Qing; Zhang, Peng; Yang, Zhe; Liu, Weijie; Zhang, Huizhen; Chen, Ni‐Wei; Wang, Hua; Qin, Huanlong

doi:10.1136/gutjnl-2014-308392

Cited by 283 publications

(240 citation statements)

References 41 publications

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“…LncRNAs have been found to be frequently dysregulated in cancers and implicated in cancer stemness and chemoresistance (30,31). LncRNA-LET has been reported to be underexpressed in cancers of digestive system and associated with cancer metastasis (25,32,33).…”

Section: Discussionmentioning

confidence: 99%

TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer

et al. 2017

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High tumor recurrence is frequently observed in patients with urinary bladder cancers (UBCs), with the need for biomarkers of prognosis and drug response. Chemoresistance and subsequent recurrence of cancers are driven by a subpopulation of tumor initiating cells, namely cancer stem-like cells (CSCs). However, the underlying molecular mechanism in chemotherapy-induced CSCs enrichment remains largely unclear. In this study, we found that during gemcitabine treatment lncRNA-Low Expression in Tumor (lncRNA-LET) was downregulated in chemoresistant UBC, accompanied with the enrichment of CSC population. Knockdown of lncRNA-LET increased UBC cell stemness, whereas forced expression of lncRNA-LET delayed gemcitabine-induced tumor recurrence. Furthermore, lncRNA-LET was directly repressed by gemcitabine treatment-induced overactivation of TGFβ/SMAD signaling through SMAD binding element (SBE) in the lncRNA-LET promoter. Consequently, reduced lncRNA-LET increased the NF90 protein stability, which in turn repressed biogenesis of miR-145 and subsequently resulted in accumulation of CSCs evidenced by the elevated levels of stemness markers HMGA2 and KLF4. Treatment of gemcitabine resistant xenografts with LY2157299, a clinically relevant specific inhibitor of TGFβRI, sensitized them to gemcitabine and significantly reduced tumorigenecity in vivo. Notably, overexpression of TGFβ1, combined with decreased levels of lncRNA-LET and miR-145 predicted poor prognosis in UBC patients. Collectively, we proved that the dysregulated lncRNA-LET/NF90/miR-145 axis by gemcitabine-induced TGFβ1 promotes UBC chemoresistance through enhancing cancer cell stemness. The combined changes in TGFβ1/lncRNA-LET/miR-145 provide novel molecular prognostic markers in UBC outcome. Therefore, targeting this axis could be a promising therapeutic approach in treating UBC patients.

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Section: Discussionmentioning

confidence: 99%

TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer

et al. 2017

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“…Numerous studies have shown the molecular mechanisms linked to CRC [6][7][8][9]. Tumor hypoxia is a pathological hallmark that may be correlated with metabolism, the activation of cell signaling, angiogenesis, differentiation, necrosis or cell apoptosis, tumor development and aggressiveness, etc [10][11][12].. Additionally, tumor hypoxia can have an adverse impact on the prognosis of some cancers (i.e., invasive breast cancer or cervical cancer) and the efficacy of chemo-and radiotherapy [13,14].…”

Section: Introductionmentioning

confidence: 99%

Association Between Hypoxia-Inducible Factor-2α (HIF-2α) Expression and Colorectal Cancer and Its Prognostic Role: a Systematic Analysis

Han

Huang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Although some studies showed that HIF-2α expression was correlated with an unfavorable prognosis in colorectal cancer (CRC), the prognostic results remain conflicting in CRC. The present study was performed to evaluate the association between HIF-2α expression and the clinicopathological features of this disease and to examine the potential prognostic role of HIF-2α expression in CRC. Methods: Pooled odds ratios (ORs) or hazard ratios (HRs) were calculated from available publications, The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets. Trial sequential analysis (TSA) was used to estimate the required sample information. Results: HIF-2α protein expression was more frequent in CRC than in normal colonic tissues (OR = 150.49, P < 0.001), higher in male than female CRC patients (OR = 1.47, P = 0.008), and lower in high-grade than low-grade CRC (OR = 0.49, P = 0.029). TSA verified the reliability of the above results. HIF-2α expression was not linked to the prognosis of CRC in overall survival (OS), disease-specific survival (DSS), metastasis-free survival, and relapse-free survival, and no significant correlation was found between HIF-2α alteration and OS or disease-free survival (DFS) of CRC. Expression of both HIF-2α and vascular endothelial growth factor (VEGFA, VEGFB, or VEGFC) was associated with a poor metastasis-free survival of CRC (HR = 6.95, HR = 113.51, and HR = 8.11, respectively). No association was observed between HIF-2α expression and DFS in other cancers, but HIF-2α expression was correlated with a worse DFS of CRC (HR = 1.23, P = 0.037). Moreover, HIF-2α expression was linked to a good survival benefit in some cancers (B-cell lymphoma and lung adenocarcinoma: OS, multiple myeloma: DSS, breast cancer: distant metastasis-free survival, liposarcoma: distant recurrence-free survival) (all HRs < 1, Ps < 0.05). Conclusions: HIF-2α expression may be associated with the carcinogenesis of CRC, which is higher in males

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“…HOX transcript antisense RNA (HOTAIR), a lncRNA promoting tumorigenesis and metastasis cancers including HCC [74,75], could act as molecular scaffold for recruitment of histone methyltransferase such as complexes PRC2 and LSD1, then reprograms chromatin states by coupling histone H3K27 methylation and H3K4 demethylation to specify the pattern of histone modifications on target genes, suggesting a single lncRNA could act as an epigenetic modifying platform for distinct histone modification complexes simultaneously [76,77]. Noteworthy, the colorectal cancer-associated lncRNACCAL, depicted as a key regulator of the progression of colorectal cancer, might be induced by histone H3 methylation in colorectal cancer, further inferring the potential regulatory interplay of histone methylation and lncRNA in cancer [78].…”

Section: Long Noncoding Rna and Histone Methylationmentioning

confidence: 95%

Long noncoding RNA, the methylation of genomic elements and their emerging crosstalk in hepatocellular carcinoma

Yuan

Zhang

et al. 2016

Cancer Letters

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Long non-coding RNA CCAL regulates colorectal cancer progression by activating Wnt/β-catenin signalling pathway via suppression of activator protein 2α

Abstract: Our results suggest that CCAL is a crucial oncogenic regulator involved in CRC tumorigenesis and progression.

Cited by 283 publications

References 41 publications

TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer

TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer

Association Between Hypoxia-Inducible Factor-2α (HIF-2α) Expression and Colorectal Cancer and Its Prognostic Role: a Systematic Analysis

Long noncoding RNA, the methylation of genomic elements and their emerging crosstalk in hepatocellular carcinoma

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