bims-lorfki 2021-02-21 papers

Issue of 2021‒02‒21
four papers selected by
Nikita Dewani
Max Delbrück Centre for Molecular Medicine

Cancer Cell Int. 2021 Feb 16. 21(1): 110

Long noncoding RNAs as tumorigenic factors and therapeutic targets for renal cell carcinoma.

Approximately 338,000 patients are diagnosed with kidney cancer worldwide each year, and renal cell carcinoma (RCC), which is derived from renal epithelium, accounts for more than ninety percent of the malignancy. Next generation RNA sequencing has enabled the identification of novel long noncoding RNAs (lncRNAs) in the past 10 years. Recent studies have provided extensive evidence that lncRNAs bind to chromatin modification proteins, transcription factors, RNA-binding proteins and microRNAs, and thereby modulate gene expression through regulating chromatin status, gene transcription, pre-mRNA splicing, mRNA decay and stability, protein translation and stability. In vitro and in vivo studies have demonstrated that over-expression of oncogenic lncRNAs and silencing of tumor suppressive lncRNAs are a common feature of human RCC, and that aberrant lncRNA expression is a marker for poor patient prognosis, and is essential for the initiation and progression of RCC. Because lncRNAs, compared with mRNAs, are expressed in a tissue-specific manner, aberrantly expressed lncRNAs can be better targeted for the treatment of RCC through screening small molecule compounds which block the interaction between lncRNAs and their binding proteins or microRNAs.

Keywords: Gene expression; Long noncoding RNA; Prognosis; Renal cell carcinoma; Tumor initiation; Tumor progression

DOI: https://doi.org/10.1186/s12935-021-01805-2

Am J Physiol Cell Physiol. 2021 Jan 27.

Suppression of lncRNA HOTAIR alleviates RCC angiogenesis through regulating miR-126/EGFL7 axis.

Yan-Ping Guo, Zhi-Feng Wang, Na Li, Qian-Qian Lei, Qiong Cheng, Li-Gang Shi, Sheng-Li Zhou, Xin-Hua Wang, Yang Sun, Ling-Fei Kong.

BACKGROUND: Renal cell carcinoma (RCC) has the highest mortality rate among urological cancers and tumor angiogenesis which plays critical roles in RCC progresss. Epidermal growth factor-like domain multiple 7 (EGFL7) has been recently identified as a regulator in RCC tumor angiogenesis and progression. Long non-coding RNA (LncRNA) HOTAIR has been considered as a pro-oncogene in multiple cancers, but its precise mechanism of tumor angiogenesis has rarely been reported. MicroRNA-126 (miR-126) functions as a tumor suppressor in RCC. However, the underlying tumor angiogenesis mechanism of HOTAIR/miR-126 axis in RCC has not been studied.METHODS: The proliferation, migration, angiogenesis, and the expression of EGFL7 and related proteins in extracellular signal-regulated kinase (ERK) / activators of transcription 3 (STAT3) signal pathway were determined to examine the effect and mechanism of HOTAIR and miR-126 on RCC progress. The regulatory relationship of HOTAIR and miR-126, as well as miR-126 and EGFL7 were tested using dual-luciferase reporter assay. Aenograft RCC mice model was used to examine the effect of HOTAIR on RCC tumor growth and metastasis in vivo.
RESULTS: HOTAIR knockdown and miR-126 overexpression suppressed the proliferation, migration, and angiogenesis of RCC cells. HOTAIR regulated EGFL7 expression by competitively binding to miR-126. Knockdown of HOTAIR significantly suppressed the RCC tumor progression and lung metastasis in vivo.
CONCLUSION: These findings suggest that lncRNA HOTAIR regulate RCC angiogenesis through miR-126/EGFL7 axis and provide a new perspective on the molecular pathways of angiogenesis in RCC development, which might be potential therapeutic targets for RCC treatment.

Keywords: EGFL7; HOTAIR; miR-126; renal cell carcinoma

DOI: https://doi.org/10.1152/ajpcell.00459.2019

Cell Death Dis. 2021 Feb 19. 12(2): 201

LncRNA CDKN2B-AS1 stabilized by IGF2BP3 drives the malignancy of renal clear cell carcinoma through epigenetically activating NUF2 transcription.

Xina Xie, Jiatian Lin, Xiaoqin Fan, Yuantang Zhong, Yequn Chen, Kaiqing Liu, Yonggang Ren, Xiangling Chen, Daihuan Lai, Xuyi Li, Zesong Li, Aifa Tang.

Because of the lack of sensitivity to radiotherapy and chemotherapy, therapeutic options for renal clear cell carcinoma (KIRC) are scarce. Long noncoding RNAs (lncRNAs) play crucial roles in the progression of cancer. However, their functional roles and upstream mechanisms in KIRC remain largely unknown. Exploring the functions of potential essential lncRNAs may lead to the discovery of novel targets for the diagnosis and treatment of KIRC. Here, according to the integrated analysis of RNA sequencing and survival data in TCGA-KIRC datasets, cyclin-dependent kinase inhibitor 2B antisense lncRNA (CDKN2B-AS1) was discovered to be the most upregulated among the 14 lncRNAs that were significantly overexpressed in KIRC and related to shorter survival. Functionally, CDKN2B-AS1 depletion suppressed cell proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, CDKN2B-AS1 exerted its oncogenic activity by recruiting the CREB-binding protein and SET and MYND domain-containing 3 epigenetic-modifying complex to the promoter region of Ndc80 kinetochore complex component (NUF2), where it epigenetically activated NUF2 transcription by augmenting local H3K27ac and H3K4me3 modifications. Moreover, we also showed that CDKN2B-AS1 interacted with and was stabilized by insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an oncofetal protein showing increased levels in KIRC. The Kaplan-Meier method and receiver operating curve analysis revealed that patients whose IGF2BP3, CDKN2B-AS1 and NUF2 are all elevated showed the shortest survival time, and the combined panel (containing IGF2BP3, CDKN2B-AS1, and NUF2) possessed the highest accuracy in discriminating high-risk from low-risk KIRC patients. Thus, we conclude that the stabilization of CDKN2B-AS1 by IGF2BP3 drives the malignancy of KIRC through epigenetically activating NUF2 transcription and that the IGF2BP3/CDKN2B-AS1/NUF2 axis may be an ideal prognostic and diagnostic biomarker and therapeutic target for KIRC.

DOI: https://doi.org/10.1038/s41419-021-03489-y

Front Mol Biosci. 2020 ;7 627827

LncRNA NEAT1 Promotes High Glucose-Induced Mesangial Cell Hypertrophy by Targeting miR-222-3p/CDKN1B Axis.

Lin Liao, Jie Chen, Chuanfu Zhang, Yue Guo, Weiwei Liu, Wenrui Liu, Lianxiang Duan, Ziyang Liu, Jing Hu, Jianrao Lu.

Glomerular hypertrophy is an early morphological alteration in diabetic nephropathy. Cyclin-Dependent Kinases have been shown to be required for high glucose (HG)-induced hypertrophy; however, the upstream regulators of CDKN1B in glomerular hypertrophy remain unclear. Herein we describe a novel pathway in which Long noncoding RNA (lncRNA) NEAT1 regulates the progression of mesangial cell hypertrophy via a competing endogenous RNA (ceRNA) mechanism. Real-time PCR was performed to detect the relative NEAT1 and miR-222-3p expressions and further confirmed the relationship between NEAT1 and miR-222-3p. Cell cycle was evaluated by flow cytometry. The related mechanisms were explored by Western blot, RNA immunoprecipitation and chromatin immunoprecipitation assay. We show that NEAT1 forms double stranded RNA (dsRNA) with miR-222-3p, thus limiting miR-222-3p's binding with CDKN1B. This release of CDKN1B mRNA leads to elevated CDKN1B protein expression, resulting in hypertrophy. In addition, we demonstrated that STAT3 which is activated by HG induces the transcription of NEAT1 by binding to its promoter. Our findings underscore an unexpected role of lncRNAs on gene regulation and introduce a new mode of proliferation regulation in mesangial cells.

Keywords: CDKN1B; Hypertrophy; NEAT1; ceRNA; miR-222-3p; stat3

DOI: https://doi.org/10.3389/fmolb.2020.627827