LncRNA AFAP1-AS1 Supresses miR-139-5p and Promotes Cell Proliferation and Chemotherapy Resistance of Non-small Cell Lung Cancer by Competitively Upregulating RRM2

Huang, Na; Guo, Wei; Ren, Ke; Li, Wancheng; Jiang, Yi; Sun, Jian; Dai, Wei; Zhao, Wei

doi:10.3389/fonc.2019.01103

Cited by 74 publications

(79 citation statements)

References 47 publications

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“…Long non-coding RNAs (lncRNAs) were reported to contribute the initiation and development of cancers by our and other groups (Bautista et al, 2018 ; Chang et al, 2018 ; Zhao et al, 2018 ; Huang et al, 2019 ; Li et al, 2020 ). HOX transcript antisense RNA (HOTAIR) enhances lung cancer cell invasion and motility (Zhao et al, 2014a ).…”

Section: Introductionmentioning

confidence: 84%

“…Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is considered a key marker of metastasis in lung cancer (Gutschner et al, 2013 ). The lncRNA actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1) promotes NSCLC tumorigenesis and chemoresistance (Yin et al, 2018 ; Huang et al, 2019 ). SBF2-AS1, an oncogenic lncRNA, increases NSCLC cell proliferation (Lv et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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LncRNA DHRS4-AS1 Inhibits the Stemness of NSCLC Cells by Sponging miR-224-3p and Upregulating TP53 and TET1

Yan

Zhao

et al. 2020

Front. Cell Dev. Biol.

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Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death. This study aimed to examine the roles of DHRS4-AS1/miR-224-3p signaling in the cancer cell stemness of NSCLC. Real-time PCR showed that DHRS4-AS1 was downregulated in cancerous tissues, and bioinformatics analysis revealed that high DHRS4-AS1 expression indicated a good prognosis for NSCLC patients. Sphere and colony formation assays showed that DHRS4-AS1 overexpression significantly suppressed NSCLC cell colony formation and stem cell-like properties. DHRS4-AS1 also abrogated the expression of OCT4, SOX2, CD34, and CD133, markedly inhibited the expression of epithelial-mesenchymal transition (EMT)-related factors, N-cadherin, ZEB1, and Vimentin, and increased E-cadherin expression in spheres. Furthermore, luciferase reporter assays and real-time PCR analysis demonstrated that DHRS4-AS1 and miR-224-3p were antagonistically repressed in NSCLC cells. RNA immunoprecipitation (RIP) analysis revealed that DHRS4-AS1 interacted with miR-224-3p. DHRS4-AS1 partially reversed the miR-224-3p-decreased TP53 and TET1, resulting in the inhibition of tumor growth in vivo. Finally, TP53 and TET1 were antagonistically regulated by DHRS4-AS1 and miR-224-3p in NSCLC cells. In conclusion, TP53- and TET1-associated DHRS4-AS1/miR-224-3p axis is an essential mechanism by which NSCLC modulates cancer cell stemness.

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Section: Introductionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

LncRNA DHRS4-AS1 Inhibits the Stemness of NSCLC Cells by Sponging miR-224-3p and Upregulating TP53 and TET1

Yan

Zhao

et al. 2020

Front. Cell Dev. Biol.

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“…Souglakos' study revealed that the efficacy of docetaxel/gemcitabine in lung adenocarcinoma patients was associated with RRM2 mRNA expression from 42 patients 18 . Huang and colleagues studied 44 patient samples and found that the overexpression of RRM2 promoted proliferation, inhibited apoptosis, and increased the chemotherapy resistance of NSCLC cells through upregulating EGFR expression and AKT phosphorylation 17 . Recently, Yang's team worked on 30 patients and found that RRM2 was upregulated in NSCLC tumors and cell lines, leading to poor prognosis 16 .…”

Section: Discussionmentioning

confidence: 99%

Independent prognostic implications of RRM2 in lung adenocarcinoma

Luo

Cao

et al. 2020

J. Cancer

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Background: Ribonucleoside-diphosphate reductase subunit M2 ( RRM2 ) is the catalytic subunit of ribonucleotide reductase and modulates the enzymatic activity, which is essential for DNA replication and repair. However, the role of RRM2 in lung adenocarcinoma (LUAD) remains unclear. Methods: In this study, we explored the expression pattern and prognostic value of RRM2 in LUAD across TCGA, GEO, Oncomine, UALCAN, PrognoScan, and Kaplan-Meier Plotter, and confirmed its independent prognostic value via Cox analyses. LinkedOmics and GEPIA2 were applied to investigate co-expression and functional networks associated with RRM2 . Besides, we used TIMER to assess the correlation between RRM2 and the main six types of tumor-infiltrating immune cells. Lastly, the correlations between immune signatures of immunomodulators, chemokines, and 28 tumor-infiltrating lymphocytes (TILs) and RRM2 were examined by tumor purity-corrected partial Spearman's rank correlation coefficient through TIMER portal. Results: RRM2 was found upregulated in tumor tissues in TCGA-LUAD, and validated in multiple independent cohorts. Moreover, whether in TCGA or other cohorts, high RRM2 expression was found to be associated with poor survival. Cox analyses showed that high RRM2 expression was an independent risk factor for overall survival, disease-specific survival, and progression-free survival of LUAD. Functional network analysis suggested that RRM2 regulates RNA transport, oocyte meiosis, spliceosome, ribosome biogenesis in eukaryotes, and cellular senescence signaling through pathways involving multiple cancer-related kinases and E2F family. Also, RRM2 expression correlated with infiltrating levels of B cells, CD4+ T cells, and neutrophils. Subsequent analysis found that B cells and dendritic cells could predict the outcome of LUAD. B cells were identified as an independent risk factor among six types of immune cells through Cox analyses. At last, the correlation analysis showed RRM2 correlated with 67.68% (624/922) of the immune signatures we performed. Conclusion: Our research showed that RRM2 could independently predict the prognosis of LUAD and was associated with immune infiltration. In particular, the tight relationship between RRM2 and B cell marker genes are the potential epicenter of the immune response and one of the critical factors affecting the prognosis. Our findings laid the foundation for further research on the immunomodulatory role of RRM2 in LUAD.

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“…Interestingly, RRM2 has also been involved in several ceRNA networks and its upregulation has been found to trigger cell proliferation, drug-resistance and tumor growth in LC [26,27]. Importantly, arti cial up-regulation of RRM2 in cells promoted cell viability, migration, invasion and resistance to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-520a discourages lung cancer pathogenesis and progression involving the downregulation of RRM2 and Wnt signaling deficits

Xue

Guo

Yang

2020

Preprint

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Background Increasingly evidence has noted the critical functions of microRNAs (miRNAs) in disease control including cancer progression. This paper aimed to explore the functions of miR-520a in lung cancer (LC) and the downstream molecules implicated. Methods Aberrantly expressed miRNAs in LC tissues were screened out by miRNA microarrays. miR-520a expression in LC tissues and cell lines was determined, and the correlation between miR-520a level and survival rate of patients was analyzed. Altered expression of miR-520a was introduced to evaluate its function in LC cell malignant behaviors. The target mRNA and the potential signaling pathway mediated by miR-520a were figured out. Xenograft tumors were induced in mice to test the role of miR-520a in tumorigenesis in vivo. Results Poor expression of miR-520a was found in LC tissues and cell lines. A higher miR-520a level indicated a better survival rate in LC patients. Overexpression of miR-520a led to declines in cell viability, proliferation, migration, invasion and resistance to apoptosis. The target mRNAs of miR-520a were enriched on the Wnt signaling. miR-520a inactivated the Wnt pathway. miR-520a could bind to RRM2 and downregulate RRM2 expression in LC cells. Overexpression of RRM2 promoted the malignant behaviors of cancer cells, but this promotion was inhibited by miR-520a. Overexpression of miR-520a also inhibited the tumor growth and metastasis in nude mice. Conclusion The present study provided evidence that miR-520a could inhibit LC progression through RRM2 down-regulation and Wnt signaling deficit. This paper may offer novel ideas concerning LC treatment.

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LncRNA AFAP1-AS1 Supresses miR-139-5p and Promotes Cell Proliferation and Chemotherapy Resistance of Non-small Cell Lung Cancer by Competitively Upregulating RRM2

Cited by 74 publications

References 47 publications

LncRNA DHRS4-AS1 Inhibits the Stemness of NSCLC Cells by Sponging miR-224-3p and Upregulating TP53 and TET1

LncRNA DHRS4-AS1 Inhibits the Stemness of NSCLC Cells by Sponging miR-224-3p and Upregulating TP53 and TET1

Independent prognostic implications of RRM2 in lung adenocarcinoma

MicroRNA-520a discourages lung cancer pathogenesis and progression involving the downregulation of RRM2 and Wnt signaling deficits

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