LncRNA GAU1 Induces GALNT8 Overexpression and Potentiates Colorectal Cancer Progression.
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ABSTRACT:
SUBMITTER: Tang X
PROVIDER: S-EPMC8233076 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mounting evidences have indicated that long noncoding RNAs (lncRNAs) play pivotal roles in human diseases, especially in cancers. Recently, TINCR was proposed to be involved in tumor progression. However, its role in colorectal cancer (CRC) remains elusive. In our study, we found that SP1-induced TINCR was significantly upregulated in CRC tissues and cell lines. Moreover, cox multivariate survival analysis revealed that high TINCR was an independent predictor of poor overall survival (OS). Functionally, knockdown of TINCR obviously suppressed CRC cells proliferation, migration and invasion in vitro, and inhibited CRC cells growth and metastasis in vivo. Mechanistically, we identified TINCR could act as a miR-7-5p sponge using RNA pull down, luciferase reporter and RIP assays. Furthermore, we showed that TINCR might promote CRC progression via miR-7-5p-mediated PI3K/Akt/mTOR signaling pathway. Lastly, we revealed that plasma TINCR expression was upregulated in CRC when compared to healthy controls and could be a promising diagnostic biomarker for CRC. Based on above results, our data indicated that TINCR might serve as a potential diagnostic and prognostic biomarker for CRC.
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Project description:BackgroundColorectal cancer is a digestive tract malignant tumor, ranking the second mortality and the third incidence cancer worldwide. The abnormal expression of NEAT1 is related to the occurrence and development of colorectal cancer. However, the specific mechanism of NEAT1 mediated-inflammatory pathway in the progression of colorectal cancer is still unclear.MethodsIn this study, expression of NEAT1 in colorectal cancer patients was analyzed by bioinformatics. Clinical samples including peripheral blood and colorectal cancer tissues were collected for qRT-PCR, Western blot, and immunohistochemistry assay. The role of NEAT1 in the colorectal cancer progression was further confirmed by both in-vivo and in-vitro functional experiments.ResultsBy bioinformatics prediction, it is found that NEAT1 expression level is significantly higher in the peripheral blood of patients with colorectal cancer and is associated with poor prognosis. In-vitro functional studies indicated that NEAT1 knockdown suppressed the proliferation and migration of colorectal cancer cells by mediating inflammatory response. In-vivo tumorigenesis experiments showed that NEAT1 knockdown suppressed tumor growth.ConclusionAbnormal high expression level of NEAT1 in colorectal cancer tissues and cells leads to poor prognosis. Mechanistically, NEAT1 triggers off the proliferation and migration of colorectal cancer cells through promoting the inflammatory reaction. Clinically, the expression level of NEAT1 in serum may be a marker for diagnosis and prognosis of colorectal cancer.
| S-EPMC9536976 | biostudies-literature
Project description:BACKGROUND:Accumulating evidences show that long noncoding RNAs (lncRNA) play essential roles in the development and progression of various malignancies. However, their functions remains poorly understood and many lncRNAs have not been defined in colorectal cancer (CRC). In this study, we investigated the role of DLEU1 in CRC. METHODS:Quantitative real-time PCR was used to detect the expression of DLEU1 and survival analysis was adopted to explore the association between DLEU1 expression and the prognosis of CRC patients. CRC cells were stably transfected with lentivirus approach and cell proliferation, migration, invasion and cell apoptosis, as well as tumorigenesis in nude mice were performed to assess the effects of DLEU1 in BCa. Biotin-coupled probe pull down assay, RNA immunoprecipitation and Fluorescence in situ hybridization assays were conducted to confirm the relationship between DLEU1 and SMARCA1. RESULTS:Here we revealed that DLEU1 was crucial for activation of KPNA3 by recruiting SMARCA1, an essential subunit of the NURF chromatin remodeling complex, in CRC. DLEU1 was indispensible for the deposition of SMARCA1 at the promoter of KPNA3 gene. Increased expression of DLEU1 and KPNA3 was observed in human CRC tissues. And higher expression of DLEU1 or KPNA3 in patients indicates lower survival rate and poorer prognosis. DLEU1 knockdown remarkably inhibited CRC cell proliferation, migration and invasion in vitro and in vivo while overexpressing KPNA3 in the meantime reversed it. CONCLUSIONS:Our results identify DLEU1 as a key regulator by a novel DLEU1/SMARCA1/KPNA3 axis in CRC development and progression, which may provide a potential biomarker and therapeutic target for the management of CRC.
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Project description:BackgroundRecent reports suggest that the long non-coding RNA LBX2 antisense RNA 1 (LBX2-AS1) acts as an important regulator in cancer progression, but its significance in colorectal cancer (CRC) remains undetermined.MethodsLBX2-AS1 expression levels in CRC were determined from the GEPIA database and CRC tissues to investigate clinical relevance. meRIP-PCR assays investigated the molecular mechanisms underlying the function of m6A in LBX2-AS1. Loss of function experiments was used to define the role of LBX2-AS1 in the progression of CRC. The ceRNA function of LBX2-AS1 was evaluated by RNA immunoprecipitation. In vitro and PDX models were used to determine if LBX2-AS1 promotes 5-fluorouracil resistance.ResultsData from the TCGA and our institutional patient cohorts established that LBX2-AS1 levels were significantly upregulated in most CRC tissues relative to normal adjacent colon tissues. Moreover, LBX2-AS1 levels were positively correlated with aggressive disease characteristics, constituting an independent prognostic indicator of overall patient survival. Mechanistic investigations suggested that the increased LBX2-AS1 in CRC was mediated by METTL3-dependent m6A methylation. In vitro experiments indicated that knockdown of LBX2-AS1 inhibited CRC proliferation, migration and invasion with this phenotype linked to LBX2-AS1-mediated regulation of AKT1, acting as a ceRNA to sponge miR-422a. Ex vivo analysis of patient-derived CRC xenografts showed that low LBX2-AS1 expression cases exhibited 5-FU responsiveness and clinical investigations confirmed that low LBX2-AS1 expression was associated with improved clinical benefits from 5-FU therapy.ConclusionsTogether these results suggest that LBX2-AS1 may serve as a therapeutic target and predictor of 5-FU benefit in CRC patients.
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Project description:Phospholipase D (PLD) is a potential therapeutic target against cancer. However, the contribution of PLD inhibition to the antitumor response remains unknown. We developed a potent and selective PLD1 inhibitor based on computer-aided drug design. The inhibitor enhanced apoptosis in colorectal cancer (CRC) cells but not in normal colonic cells, and in vitro cardiotoxicity was not observed. The inhibitor downregulated the Wnt/β-catenin signaling pathway and reduced the migration, invasion, and self-renewal capacity of CRC cells. In cancer, therapeutic engagement of immunogenic cell death (ICD) leads to more effective responses by eliciting the antitumor immunity of T cells. The CRC cells treated with the inhibitor showed hallmarks of ICD, including downregulation of "do not eat-me" signals (CD24, CD47, programmed cell death ligand 1 [PD-L1]), upregulation of "eat-me" signal (calreticulin), release of high-mobility group Box 1, and ATP. PLD1 inhibition subsequently enhanced the phagocytosis of cancer cells by macrophages through the surface expression of costimulatory molecules; as a result, the cancer cells were more susceptible to cytotoxic T-cell-mediated killing. Moreover, PLD1 inhibition attenuated colitis-associated CRC and orthotopically injected tumors, probably by controlling multiple pathways, including Wnt signaling, phagocytosis checkpoints, and immune signaling. Furthermore, combination therapy with a PLD1 inhibitor and an anti-PD-L1 antibody further enhanced tumor regression via immune activation in the tumor environment. Collectively, in this study, PLD1 was identified as a critical regulator of the tumor microenvironment in colorectal cancer, suggesting the potential of PLD1 inhibitors for cancer immunotherapy based on ICD and immune activation. PLD1 inhibitors may act as promising immune modulators in antitumor treatment via ICD.
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Project description:Tumor metastasis is the major cause of death among cancer patients, with >90% of cancer-related death attributable to the spreading of metastatic cells to secondary organs. Store-operated Ca(2+) entry (SOCE) is the predominant Ca(2+) entry mechanism in most cancer cells, and stromal interaction molecule 1 (STIM1) is the endoplasmic reticulum (ER) Ca(2+) sensor for store-operated channels. Here we reported that the STIM1 was overexpressed in colorectal cancer (CRC) patients. STIM1 overexpression in CRC was significantly associated with tumor size, depth of invasion, lymph node metastasis status and serum levels of carcinoembryonic antigen. Furthermore, ectopic expression of STIM1 promoted CRC cell motility, while depletion of STIM1 with short hairpin RNA inhibited CRC cell migration. Our data further suggested that STIM1 promoted CRC cell migration through increasing the expression of cyclooxygenase-2 (COX-2) and production of prostaglandin E2 (PGE2). Importantly, ectopically expressed COX-2 or exogenous PGE2 were able to rescue migration defect in STIM1 knockdown CRC cells, and inhibition of COX-2 with ibuprofen and indomethacin abrogated STIM1-mediated CRC cell motility. In short, our data provided clinicopathological significance for STIM1 and SOCE in CRC progression, and implicated a role for COX-2 in STIM1-mediated CRC metastasis. Our studies also suggested a new approach to inhibit STIM1-mediated metastasis with COX-2 inhibitors.
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Project description:Background:NLIPMT, as a tumor suppressive lncRNA, has only been investigated in breast cancer, while its roles in other types of cancer remain unknown. This study aimed to explore the role of NLIPMT in colorectal cancer (CRC). Methods:Expression levels of NLIPMT and TGF-?1 in two types of CRC tissue (Non-tumor tissues and tumor tissues) were measured and compared by qRT-PCR and paired t-test, respectively. Correlations between the expression of NLIPMT and TGF-?1 were analyzed by performing linear regression. The effects of transfections on cell invasion and migration were evaluated by Transwell assays. Results:We found that NLIPMT was downregulated, while TGF-?1 was upregulated in CRC. In CRC tumor, a negative correlation was found between the expression of NLIPMT and TGF-?1. In CRC cells, overexpression of NLIPMT resulted in downregulation, while silencing of NLIPMT resulted in upregulation of TGF-?1. Analysis of cell invasion and migration showed that overexpression of NLIPMT suppressed the tumor cell invasion and migration. In contrast, overexpression of TGF-?1 could promote CRC cell invasion and migration and also reduce the role of NLIPMT. Through the overall survival evaluation, NLIPMT-high groups of CRC represented better survival rate compared to that of the NLIPMT-low group patients. Conclusion:The expression of lncRNA NLIPMT was negatively correlated with TGF-?1 in CRC. Overexpression of NLIPMT inhibited the colorectal cancer cell migration and invasion by downregulating TGF-?1. Furthermore, the expression of NLIPMT in CRC patients predicted better prognosis, which suggested that NLIPMT could be considered as a novel diagnosis biomarker.
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Project description:Colorectal cancer is one of the most commonly diagnosed malignancies among males and females worldwide. Although China is a country with a low incidence of colorectal cancer, with the improvement of China's economy and lifestyle changes, the incidence rate in China has generally increased in recent years, and the morbidity and mortality of colorectal cancer rank fifth among those of all malignant tumours. Furthermore, despite recent improvements in screening strategies and treatments for colorectal cancer, the prognosis of advanced colorectal cancer is still poor, mainly due to the recurrence or distant metastasis of this disease. Thus, colorectal cancer still seriously threatens the health and life of people and is a major public health problem worthy of further study. Recently, accumulating evidence has revealed that colorectal carcinogenesis might be a multistep process driven by progressive genetic abnormalities, including changes in lncRNA expression. Moreover, a large number of studies have discovered and studied the abnormal expression of lncRNAs in colorectal cancer, providing a promising target for the diagnosis and treatment of colorectal cancer, which will promote human understanding of the pathogenesis of colorectal cancer and improve diagnosis and treatment. Therefore, in the present review, we mainly summarize the present status of colorectal cancer, the characteristics, functions and clinical perspectives of lncRNAs, and the current therapeutic methods used for colorectal cancer, especially the application of lncRNAs in the treatment of colorectal cancer. It is hoped that this review will give readers a new understanding of the roles of lncRNAs in colorectal cancer.
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Project description:Colorectal cancer (CRC) is a tumor type characterized by high patient morbidity and mortality. It has been reported that long non-coding (lncRNA) LUNAR1 (LUNAR1) participates in the regulation of tumor progression, such as diffuse large B-cell lymphoma. However, its role and underlying mechanisms in CRC progression have not been elucidated. The present study was designed to investigate the underlying mechanisms by which LUNAR1 regulates CRC progression. RT-qPCR and Pearson's correlation analysis revealed that LUNAR1 was highly expressed and was negatively associated with the overall survival of CRC patients. Moreover, CCK-8, clone formation, wound-healing migration, Transwell chamber and FACs assay analyses showed that LUNAR1 knockdown inhibited CRC cell proliferation, migration and invasion, while accelerating cell apoptosis. Additionally, LUNAR1 was found to function as a sponge of miR-495-3p, which was predicted by TargetScan and confirmed by luciferase reporter assay. Furthermore, functional studies indicated that miR-495-3p overexpression inhibited CRC cell proliferation, migration and invasion, while accelerating cell apoptosis. In addition, bioinformatics and luciferase reporter assays showed that miR-495-3p was found to negatively target Myc binding protein (MYCBP), and functional research showed that LUNAR1 accelerated CRC progression via the miR-495-3p/MYCBP axis. In conclusion, LUNAR1 accelerates CRC progression via the miR-495-3p/MYCBP axis, indicating that LUNAR1 may serve as a prognostic biomarker for CRC patients.
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Project description:The gene encoding migration and invasion inhibitory protein (MIIP), located on 1p36.22, is a potential tumour suppressor gene in glioma. In this study, we aimed to explore the role and mechanism of action of MIIP in colorectal cancer (CRC). MIIP protein expression gradually decreased along the colorectal adenoma-carcinoma sequence and was negatively correlated with lymph node and distant metastasis in 526 colorectal tissue samples (p < 0.05 for all). Analysis of The Cancer Genome Atlas (TCGA) data showed that decreased MIIP expression was significantly associated with MIIP hemizygous deletion (p = 0.0005), which was detected in 27.7% (52/188) of CRC cases, and associated with lymph node and distant metastasis (p < 0.05 for both). We deleted one copy of the MIIP gene in HCT116 CRC cells using zinc finger nuclease technology and demonstrated that MIIP haploinsufficiency resulted in increased colony formation and cell migration and invasion, which was consistent with the results from siRNA-mediated MIIP knockdown in two CRC cell lines (p < 0.05 for all). Moreover, MIIP haploinsufficiency promoted CRC progression in vivo (p < 0.05). Genomic instability and spectral karyotyping assays demonstrated that MIIP haploinsufficiency induced chromosomal instability (CIN). Besides modulating the downstream proteins of APC/CCdc20 , securin and cyclin B1, MIIP haploinsufficiency inhibited topoisomerase II (Topo II) activity and induced chromosomal missegregation. Therefore, we report that MIIP is a novel potential tumour suppressor gene in CRC. Moreover, we characterized the MIIP gene as a novel CIN suppressor gene, through altering the stability of mitotic checkpoint proteins and disturbing Topo II activity. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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