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

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.

FGFR3S249C mutation promotes chemoresistance by activating Akt signaling in bladder cancer cells.

Fibroblast growth factor receptor 3 (FGFR3) is a high frequency mutant gene in bladder cancer (BCa) and has become a promising therapeutic target due to its involvement in cell proliferation and migration. However, whether and how FGFR3 mutations affects BCa cell chemosensitivity is unknown. The current study aimed to elucidate the role of the FGFR3S249C mutation in the development of chemoresistance in BCa cells. The results revealed that 97-7 (FGFR3S249C) cells had decreased sensitivity to cisplatin compared with 5637 (FGFR3WT) and T24 (FGFR3WT) cells. The ratio of phosphorylated-Akt/total-Akt was higher in 97-7 (FGFR3S249C) cells, which was reversed by knockdown of FGFR3. Furthermore, inhibition of Akt signaling by GDC0068 or LY294002 increased the cisplatin sensitivity of 97-7 (FGFR3S249C) cells. GDC0068 or LY294002 was also revealed to augment the effects of cisplatin on 97-7 (FGFR3S249C) cell proliferation and apoptosis. The results of the present study demonstrated that the FGFR3S249C mutation promotes chemoresistance in BCa cells by activating the Akt signaling pathway. The FGFR3S249C mutation may therefore be used as a predictor of chemosensitivity in patients with BCa.

A novel lncRNA NR4A1AS up-regulates orphan nuclear receptor NR4A1 expression by blocking UPF1-mediated mRNA destabilization in colorectal cancer.

Long non-coding RNAs (lncRNAs) play important roles in tumorigenesis and cancer progression. The orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) acts as an oncogene, and is involved in colorectal cancer (CRC) development. However, the mechanism through which lncRNA regulates NR4A1 expression remains unknown. We aimed to identify lncRNAs that regulate NR4A1 and assess their underlying mechanisms in CRC. We first identified an antisense lncRNA of NR4A1 that was up-regulated in CRC tissues and cells with rapid amplification of cDNA ends (RACE), and designated it as NR4A1AS. Spearman correlation analysis showed that NR4A1AS was positively correlated with NR4A1 mRNA levels in 37 CRC tissues. Mechanistically, NR4A1AS stabilized NR4A1 mRNA by forming RNA-RNA complexes via partial base-pairing and up-regulated NR4A1 expression in CRC cells. RNA immunoprecipitation (RIP) assays revealed that knockdown of NR4A1AS expression by siRNA enhanced up-frameshift 1 (UPF1) recruitment to NR4A1 mRNA, thereby decreasing NR4A1 mRNA stability. Moreover, depletion of NR4A1AS was found to mimic the effect of NR4A1 knockdown, specifically by suppressing cell proliferation, migration and invasion, and inducing apoptosis and cell cycle arrest. Accordingly, restoring NR4A1 expression ameliorated the effects of NR4A1AS knockdown on tumor growth and metastasis of CRC cells in vitro and in vivo Thus, we conclude that NR4A1AS up-regulates NR4A1 expression by forming RNA-RNA complexes and blocking UPF1-mediated mRNA destabilization, and it functions in tumor growth and metastasis of CRC cells at least partly through regulating NR4A1, suggesting that NR4A1AS might be as a potential target for RNA-based anti-CRC drug studies.

Decreased expression of SRY-box containing gene 30 is related to malignant phenotypes of human bladder cancer and correlates with poor prognosis.

BACKGROUND: In human pulmonary malignancies, the SRY-box containing gene 30 (SOX30) is a known cancer-suppressing gene. Nevertheless, its molecular role and clinical effects remains unknown in bladder cancer. METHODS: SOX30 mRNA expression was quantified in bladder cancer tissue, paired adjacent normal tissue, and cell lines with qRT-PCR. SOX30 protein expression in BC tissue and cell lines was evaluated via western blotting and immunohistochemistry. In addition, the clinical and prognostic significance of SOX30 in BC were assessed using Kaplan-Meier analysis. Furthermore, we measured cell migration and invasion, cell proliferation and cell apoptosis by means of a Transwell assay, cell counting kit-8 along with flow cytometry, respectively. RESULTS: Expression levels of SOX30 were markedly lower in BC cells and tumor tissues than in adjacent noncancerous tissues. Moreover, clinicopathological analyses showed that low SOX30 expression was positively related to an advanced tumor, node, and metastasis (TNM) stage. Furthermore, low SOX30 expression conferred reduced survival rates (P < 0.05). Functional analyses revealed that SOX30 overexpression attenuated cell proliferation, invasion, and migration, while promoting apoptosis in BC cells. CONCLUSIONS: SOX30 displays tumor suppressive behavior, warranting future investigations into its therapeutic potential in the treatment of BC.

Long noncoding RNA ANRIL as a novel biomarker of lymph node metastasis and prognosis in human cancer: a meta-analysis.

Dysregulation of the long noncoding RNA antisense noncoding RNA in the INK4 locus (ANRIL) has been reported in various solid tumors. We performed a synthetic analysis to clarify the clinical value of ANRIL as a prognostic indicator in malignant tumors. Article collection was conducted using several electronic databases, including PubMed, Web of Science, Medline, OVID and Embase (up to July 14 2017). Thirteen original studies and 1172 total patients were included in the meta-analysis. There was a significant positive association between the high expression level of ANRIL and lymph node metastasis (OR = 4.77, 95% CI: 2.30-9.91, P < 0.001) by a random effects model (I2 = 73.2, P = 0.001) and negative association with poor grade cancer (OR = 3.44, 95% CI: 1.68-7.08) by a random-effects model (I2 = 77.9, P = 0.000). The results of the meta-analysis showed that overexpression of ANRIL is positively related to poor overall survival (OS) (pooled HR = 2.12, 95% CI: 1.78-2.53, P < 0.0001) by a fixed-effects model (I2 = 0%, P = 0.654) and poor disease-free survival (DFS) (HR = 2.10, 95% CI: 1.51-2.92, P < 0.001) by a fixed-effects model (I2 = 13.3%, P = 0.315) in human solid cancers. Statistically significant associations were also found with cancer type, analysis method, sample size, and follow-up time. In conclusion, ANRIL may serve as a novel biomarker for indicating lymph node metastasis and prognosis in human cancer.

Long non-coding PANDAR as a novel biomarker in human cancer: A systematic review.

OBJECTIVES: Long non-coding RNAs (lncRNAs) are characterized as a group of RNAs that more than 200 nucleotides in length and have no protein-coding function. More and more evidences provided that lncRNAs serve as key molecules in the development of cancer. Deregulation of lncRNAs functions as either oncogenes or tumour suppressor genes in various diseases. Recently, increasing studies about PANDAR in cancer progression were reported. In our review, we will focus on the current research on the character of PANDAR include the clinical management, tumour progression and molecular mechanisms in human cancers. MATERIALS AND METHODS: We summarize and analyze current studies concerning the biological functions and mechanisms of lncRNA PANDA in tumour development. The related studies were obtained through a systematic search of Pubmed. RESULTS: PANDAR was a well-characterized oncogenic lncRNA and widely overexpressed in many tumours. PANDAR is upregulated in many types of cancer, including colorectal cancer, lung cancer, renal cell carcinoma, cholangiocarcinoma, osteosarcoma, thyroid cancer and other cancers. Upregulation of PANDAR was significantly associated with advanced tumour weights, TNM stage and overall survival. Furthermore, repressed of PANDAR would restrain proliferation, migration and invasion. CONCLUSION: PANDAR may act as a powerful tumour biomarker for cancer diagnosis and treatment.

TMEM106a is a Novel Tumor Suppressor in Human Renal Cancer.

BACKGROUND/AIMS: In recent years the diagnosis and management of renal cancer has changed greatly, although the mechanism is still elusive. TMEM106a is a conserved type II transmembrane protein which is a key factor to regulate macrophage activation. Its inactivation in gastric cancer is frequently observed to be associated with poor prognosis. The role of TMEM106a in renal cancer remained unclear. METHODS: TMEM106a expression profiling was performed in a panel of renal cancer cell lines and primary renal tissue cells. Then TMEM106a was overexpressed by a viral system in a renal cancer cell line with low level of TMEM106a. This stable cell line was assessed in multiple cell growth and migration assays. The results from TMEM106a overexpressing cell line were then confirmed with primary renal cells by siRNA knockdown of TMEM106a. RESULTS: TMEM106a expression level was reduced in renal cancer cells compared to normal primary renal cells. Restoration of TMEM106a expression in TMEM106a-low renal cancer cells resulted in attenuated proliferation, reduced cell migration and enhanced caspase 3 dependent apoptosis compared to control cells. TMEM106a knockdown in primary renal cells led to increased colony formation compared to the control cells with scrambled siRNA transfection. CONCLUSION: TMEM106a is a novel tumor suppressor in renal cancer.

Stromal antigen 2 functions as a tumor suppressor in bladder cancer cells.

Stromal antigen 2 (STAG2) is a subunit of the cohesion complex that plays an important role in the normal segregation of sister chromatids during mitosis or meiosis. However, the effect of STAG2 on the bladder cancer cell proliferation, migration, and invasion has not yet been fully clarified. In this study, we aimed to characterize STAG2 expression and functional significance in BC and adjacent normal tissue. Notably, STAG2 expression was markedly lower in BC cells and tumor tissues than their normal counterparts at the gene and protein levels. Moreover, clinicopathological analysis showed that the low STAG2 expression is associated with TNM stage. Functional analysis demonstrated that STAG2 overexpression attenuated cell proliferation via G1-phase arrest, invasion, and migration, and promoted apoptosis in BC cell lines, while the opposite was observed with STAG2 knockdown cells. Furthermore, STAG2 overexpression upregulated E-cadherin, caspase-3, and caspase-7 and downregulated vimentin, matrix metalloproteinase (MMP)2, and MMP9. Collectively, these data suggest that STAG2 acts as a tumor suppressor gene in bladder cancer and may be a potential therapeutic target in BC.