RNAa and Vector-Mediated Overexpression of DIRAS1 Suppresses Tumor Growth and Migration in Renal Cell Carcinoma

Xu, Xin; Li, Jiangfeng; Wang, Song; Zheng, Xiangyi; Xie, Liping

doi:10.1016/j.omtn.2018.07.019

Cited by 9 publications

(12 citation statements)

References 24 publications

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“…Functionally, several studies showed that DIRAS-1 acts as a potential tumor suppressor by inhibiting cell proliferation and cell viability in different types of cancer, such as renal cell carcinoma, colorectal cancer, murine ovarian cancer cells, and esophageal squamous cell carcinoma, as well as gliomas [2,[4][5][6] and that DIRAS-1 can also suppress tumor growth in nude mice [7]. However, we did not observe an impact of DIRAS-1 overexpression on cell proliferation in the two glioma cell lines analyzed.…”

Section: Discussionmentioning

confidence: 99%

“…The DIRAS-1 gene is also known as Rig (Ras-related inhibitor of cell growth) and is located on chromosome band 19p13.3, whereas the DIRAS-2 gene is located on chromosome band 9q22.2 [1,2]. DIRAS-1, in contrast to common oncogenic small GTPases like Ras or Rho family members [3], has been reported as a potential tumor suppressor in human glioblastoma [2], colorectal cancer [4], renal cell carcinoma [5], and ovarian cancer [6], and reduced expression of DIRAS-1 predicts poor prognosis in esophageal squamous cell carcinoma [7]. Bergom and colleagues more closely analyzed the tumor suppressive mechanisms of DIRAS-1 and showed that DIRAS-1 binds to the noncanonical guanine nucleotide exchange factor SmgGDS (Rap1 GTPase-GDP dissociation stimulator 1 = RAP1GDS1) and acts similarly to a dominant-negative small GTPase [3].…”

Section: Introductionmentioning

confidence: 99%

“…Since DIRAS-1 expression is frequently reduced or lost in malignant tissues, more SmgGDS is available to interact with and activate pro-oncogenic GTPases [3]. Downregulation of DIRAS-1 expression was reported to be partly due to aberrant promoter methylation in esophageal squamous cell carcinoma, renal cell carcinoma, and colorectal cancer [4,5,7] and increased DIRAS-1 expression was shown in one renal cell carcinoma cell line after treatment with a histone deacetylase inhibitor [8].…”

Section: Introductionmentioning

confidence: 99%

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Frequent Epigenetic Inactivation of DIRAS-1 and DIRAS-2 Contributes to Chemo-Resistance in Gliomas

Rothhammer-Hampl

Liesenberg

Hansen

et al. 2021

Cancers

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We previously reported that DIRAS-3 is frequently inactivated in oligodendrogliomas due to promoter hypermethylation and loss of the chromosomal arm 1p. DIRAS-3 inactivation was associated with better overall survival. Consequently, we now investigated regulation and function of its family members DIRAS-1 and DIRAS-2. We found that DIRAS-1 was strongly downregulated in 65% and DIRAS-2 in 100% of analyzed glioma samples compared to non-neoplastic brain tissue (NNB). Moreover, a significant down-regulation of DIRAS-1 and -2 was detected in glioma data obtained from the TCGA database. Mutational analyses did not reveal any inactivating mutations in the DIRAS-1 and -2 coding regions. Analysis of the DIRAS-1 and -2 promoter methylation status showed significantly higher methylation in IDH-mutant astrocytic and IDH-mutant and 1p/19q-codeleted oligodendroglial tumors compared to NNB. Treatment of U251MG and Hs683 glioblastoma cells lines with 5-azacytidine led to significant re-expression of DIRAS-1 and -2. For IDH-wild-type primary gliomas, however, we did not observe significantly elevated DIRAS-1 and -2 promoter methylation levels, but still detected strong downregulation of both DIRAS family members. Additional analyses revealed that DIRAS-1 and -2 expression was also regulated by histone modifications. We observed a shift towards promoter heterochromatinization for DIRAS-1 and less promoter euchromatinization for DIRAS-2 in IDH-wild-type glioblastomas compared to controls. Treatment of the two glioblastoma cell lines with a histone deacetylase inhibitor led to significant re-expression of DIRAS-1 and -2. Functionally, overexpression of DIRAS-1 and -2 in glioblastoma cells translated into significantly higher sensitivity to lomustine treatment. Analyses of DNA damage markers revealed that DIRAS-1 and -2 may play a role in p53-dependent response to alkylating chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Frequent Epigenetic Inactivation of DIRAS-1 and DIRAS-2 Contributes to Chemo-Resistance in Gliomas

Rothhammer-Hampl

Liesenberg

Hansen

et al. 2021

Cancers

View full text Add to dashboard Cite

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“…Western blot analysis was performed as previously reported [ 16 ], with the following primary immunoblotting antibodies: anti-GAPDH ((10494-1-AP, Proteintech) and anti-ARNTL2 (ab221557, abcam). After transfection with RNA duplex (50 nM) for 24 h, 786-O or Caki-1 cells were performed colony formation and wound healing assay as previously reported [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

Upregulation of ARNTL2 is associated with poor survival and immune infiltration in clear cell renal cell carcinoma

Wang

Ying

et al. 2021

Cancer Cell Int

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Background Aryl hydrocarbon receptor nuclear translocator like 2 (ARNTL2) is a member of the PAS superfamily. Previous studies explored the carcinogenic roles of transcription factor ARNTL2 in human malignancies. However, its roles in ccRCC have not been elucidated. This study sought to explore the roles of ARNTL2 in ccRCC and determine its correlations with tumor immunity. Methods The expression of ARNTL2 was analyzed using the GEO, TCGA and GTEx database, and verified in ccRCC tissue samples and cell lines by qRT-PCR and western blot analysis. Kaplan–Meier survival curve analysis, Cox regression analysis (including univariate and multivariate analysis) was utilized to evaluate the prognostic values of ARNTL2. Potential biological mechanisms of ARNTL2 were explored using GSEA method. Colony formation and wound healing assays were conducted to explore the oncogenic role of ARNTL2 in ccRCC. ssGSEA and xCell algorithm were used to explore the correlation between ARNTL2 expression and tumor immune microenvironment (TIME). Results ARNTL2 was significantly upregulated in ccRCC tissues and cell lines compared to normal kidney tissues and cell line. Enhanced expression of ARNTL2 was strongly linked to advanced clinical stage and unfavorable overall survival in ccRCC. ARNTL2 was determined as an independent prognostic marker through cox regression analysis. A prognostic nomogram was constructed to predict 1-, 3- and 5-year overall survival of ccRCC patients by integrating ARNTL2 expression with other clinicopathologic variables. GSEA analysis showed that focal adhesion, T cell receptor, cell cycle, and JAK-STAT signaling pathway were significantly enriched in high ARNTL2 samples. Silencing of ARNTL2 suppressed the colony formation ability and wound healing efficacy of ccRCC cell lines. xCell analysis showed that high expression level of ARNTL2 exhibited an immune infiltration status similar to CD8 + inflamed ccRCC subtype, which was characterized by high infiltration level of CD8 + T cell and high expression level of the immune escape biomarkers such as PD-L1, PD-L2, PD1 and CTLA4. Conclusion ARNTL2 is an independent adverse predictor of ccRCC patient survival. High expression level of ARNTL2 is associated with immune infiltration, and may be a novel therapeutic target in ccRCC.

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“…DIRAS1 contributed to repressed colony formation and cell activities in ESCC [20]. DIRAS1 silencing facilitated tumor growth, augmented cancer cell survival and metastasis, and suppressed apoptosis [34]. In conclusion, DIRAS1 depletion partially annulled the promotive effect of LINC00261 on EC cell radiosensitivity.…”

Section: Discussionmentioning

confidence: 83%

LINC00261 Inhibits Esophageal Cancer Radioresistance By Downregulating microRNA-552-3p And Promoting DIRAS1

Yang

Bian

2021

Preprint

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Background: Esophageal cancer (EC) is a life-threatening tumor with a high increasing incidence rate. Long intergenic non-protein coding RNAs (LINCs) are widely researched in EC. This study set out to investigate the role of LINC00261 in EC radioresistance.Methods: Radioresistant EC cell lines TE-1-R and TE-5-R were established using TE-1 and TE-5 cells. LINC00261, microRNA (miR)-552-3p, and DIRAS1 expression in EC tissues and adjacent normal tissues and EC cells was evaluated. Then, survival fraction (SF), colony formation, apoptosis, and γ-H2AX expression were analyzed. The binding relation between LINC00261 and miR-552-3p and between miR-552-3p and DIRAS1 were detected. Eventually, xenograft transplantation was applied to confirm the effect of LINC00261 on EC radioresistance in vivo.Results: LINC00261 and DIRAS1 were weakly expressed in EC tissues and cells, but miR-552-3p was overexpressed. For EC cells with X-ray radiation, overexpression of LINC00261 reduced SF and cell viability, strengthened γ-H2AX expression, and promoted apoptosis, which were all counteracted by miR-522-3p overexpression or DIRAS1 silencing. Mechanically, the binding relation between LINC00261 and miR-552-3p and between miR-552-3p and DIRAS1 were verified. In addition, LINC00261 overexpression suppressed tumor growth and reduced EC radioresistance in vivo.Conclusion: LINC00261 could suppress EC radioresistance via the competing endogenous RNA network to sponge miR-552-3p and upregulate DIRAS1 transcription.

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RNAa and Vector-Mediated Overexpression of DIRAS1 Suppresses Tumor Growth and Migration in Renal Cell Carcinoma

Cited by 9 publications

References 24 publications

Frequent Epigenetic Inactivation of DIRAS-1 and DIRAS-2 Contributes to Chemo-Resistance in Gliomas

Frequent Epigenetic Inactivation of DIRAS-1 and DIRAS-2 Contributes to Chemo-Resistance in Gliomas

Upregulation of ARNTL2 is associated with poor survival and immune infiltration in clear cell renal cell carcinoma

LINC00261 Inhibits Esophageal Cancer Radioresistance By Downregulating microRNA-552-3p And Promoting DIRAS1

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