Long noncoding RNA PVT1: A highly dysregulated gene in malignancy

Recent studies have verified the contribution of several long noncoding RNAs (lncRNAs) in the carcinogenesis. Among the highly acknowledged lncRNAs is the human homolog of the plasmacytoma variant translocation gene, which is called PVT1. PVT1 resides near Myc oncogene and regulates the oncogenic process through modulation of several signaling pathways, such as TGF-β, Wnt/ β-catenin, PI3K/AKT, and mTOR pathways. This lncRNA has a circular form as well. Expression analyses and functional studies have appraised the oncogenic roles of PVT1 and circPVT1. Experiments in several cancer cell lines have shown that PVT1 silencing suppresses cancer cell proliferation, whereas its overexpression has the opposite effect. Its silencing has led to the accumulation of cells in the G0/G1 phase and diminished the number of cells in the S phase. Moreover, genome-wide association studies have signified the role of single nucleotide polymorphisms of this lncRNA in conferring risk of lymphoma in different populations. In the current study, we have summarized recent data about the role of PVT1 and circPVT1 in the carcinogenesis process.     

LncRNA OIP5-AS1 predicts poor prognosis and regulates cell proliferation and apoptosis in bladder cancer

Opa-interacting protein 5 antisense RNA 1 (OIP5-AS1) is a long intergenic noncoding RNA, which has been suggested to be dysregulated in human cancers and served as tumor suppressor or promoter depending on tumor types. However, the role of OIP5-AS1 in bladder cancer was still unknown. In our study, OIP5-AS1 was overexpressed in bladder cancer, and associated with clinical progression and short overall survival. The loss-of-function studies suggested downregulation of OIP5-AS1 expression decreased cell viability, induced cell-cycle arrest and promoted cell apoptosis in bladder cancer. There was a positive association between OIP5-AS1 expression and OIP5 expression in bladder cancer tissues. Moreover, downregulation of OIP5-AS1 expression reduced messenger RNA and protein levels of OIP5 in bladder cancer cell lines. In conclusion, OIP5-AS1 is a useful biomarker for predicting clinical progression and poor prognosis and promotes cell proliferation through modulating OIP5 expression.     

Angiogenesis and prostate cancer tumor growth

The initiation of new blood vessels through angiogenesis is critical to tumor growth. Tumor cells release soluble angiogenic factors that induce neovascularization, without which nutrients and oxygen would not be available to allow tumors to grow more than 2-3 mm in diameter. This "angiogenic switch" or angiogenic phenotype requires an imbalance between proangiogenic and antiangiogenic factors since the formation of new blood vessels is highly regulated. This review discusses angiogenesis mediators, and the potential for manipulation of angiogenic factors as a practical cancer therapy, particularly in prostate cancer.     

HIF1A-AS2 predicts poor prognosis and regulates cell migration and invasion in triple-negative breast cancer

The aberrant expression of hypoxia-inducible factor 1 alpha (HIF1A)-antisense RNA 2 (HIF1A-AS2) was found in various human cancers including breast cancer. The aim of this study was to present more evidence about the role HIF1A-AS2 on triple-negative breast cancer (TNBC). In our results, HIF1A-AS2 was also found to be upregulated in TNBC tissues compared with non-TNBC tissues or adjacent normal tissues. Besides, HIF1A-AS2 expression was also elevated in TNBC cell lines compared with the normal breast epithelial cell line. Moreover, high expression of HIF1A-AS2 was associated with lymph node metastasis, distant metastasis and unfavorable histological grade in TNBC patients. Survival analysis showed a TNBC patient with high HIF1A-AS2 expression had shorter overall survival than patients with low HIF1A-AS2 expression, and HIF1A-AS2 high expression acted as an independent poor prognostic factor for overall survival in TNBC patients. The cell migration and invasion assays suggested inhibition of HIF1A-AS2 obviously depressed TNBC cell migration and invasion. In conclusion, HIF1A-AS2 serves as a novel biomarker for predicting clinical progression and prognosis in TNBC.     

Knockdown of LncRNA PVT1 inhibits tumorigenesis in non-small-cell lung cancer by regulating miR-497 expression

Plasmacytoma variant translocation1 (PVT1) was reported to be upregulated in non-small-cell lung cancer (NSCLC) tissues, serve as a promising biomarker for diagnosis and prognosis of NSCLC, and promoted NSCLC cell proliferation. However, the detailed molecular mechanism of PVT1 involved in the pathogenesis and development of NSCLC remains largely unknown. In this study, the expression levels of PVT1 and miR-497 in NSCLC cells were determined by qRT-PCR. Cell viability, invasion and apoptosis were detected by MTT assay, cell invasion assay and flow cytometry analysis, respectively. RNA immunoprecipitation (RIP) and luciferase reporter assay were performed to confirm whether PVT1 directly interacts with miR-497. A xenograft mouse model was established to confirm the effect of PVT1 on tumor growth in vivo and the underlying molecular mechanism. Our findings indicated that PVT1 was significantly upregulated and miR-497 was markedly downregulated in NSCLC cell lines. si-PVT1 effectively decreased the expression of PVT1 and increased the expression of miR-497. PVT1 knockdown remarkably inhibited cell viability, invasion and promoted apoptosis in NSCLC cells. RIP and luciferase reporter assay demonstrated that PVT1 could directly interact with miR-497. Moreover, PVT1 overexpression reversed the inhibitory effect of miR-497 on cell viability, invasion and promotion effect on apoptosis of NSCLC cells. Furthermore, in vivo experiment showed that knockdown of PVT1 inhibited tumor growth in vivo and promoted miR-497 expression. In conclusion, knockdown of PVT1 inhibited cell viability, invasion and induced apoptosis in NSCLC by regulating miR-497 expression, elucidating the molecular mechanism of the oncogenic role of PVT1 in NSCLC and providing an lncRNA-directed target for NSCLC.     

Exonuclease 1 expression is associated with clinical progression,metastasis, and survival prognosis of prostate cancer

Prostate cancer (PCa) is the most prevalent malignancy and the second leading cause of cancer-related deaths in the male population in western countries, and we explored the association between exonuclease 1 (EXO1) expression and clinical progression, metastasis (Met), and survival prognosis of PCa. EXO1 expression of high/low-metastatic patient-derived xenografts model was investigated and clinical correlation and prognosis outcomes were validated. EXO1 in high-metastatic models was significantly increased compared with low-metastatic lines. In memorial sloan-kettering cancer center (MSKCC) cohort, EXO1 expression positively correlated with PCa Met, and patients with high EXO1 had poor biochemical recurrence-free survival in primary PCa cohort. Validation in The Cancer Genome Atlas primary cohort indicated EXO1 expression was significantly associated with lymph node Met and disease-free survival. The overexpression of EXO1 is significantly associated with PCa poor survival outcome, and is a promising biomarker for PCa, especially for primary PCa. A prospective study is clearly needed to validate these findings.     

LncRNA PCAT‐1 promotes tumour growth and chemoresistance of oesophageal cancer to cisplatin

Oesophageal cancer (OC) is one of the most fatal malignancies in the world, and chemoresistance restricts the therapeutic outcome of OC. Long noncoding RNA (lncRNA) was reported to play roles in multiple cancer types. Yet, the function of lncRNA in chemoresistance of OC has not been reported. A lncRNA gene, PCAT‐1, showed higher expression in OC tissues, especially higher in secondary OC compared with normal mucosa tissues. Overexpression of PCAT‐1 increased the proliferation rate and growth of OC cells. Inhibition of PCAT‐1 decreased proliferation and growth of OC cells, and increased cisplatin chemosensitivity. In a mouse OC xenograft model, PCAT‐1 inhibition repressed OC growth in vivo. Therefore, PCAT‐1 may potentially serve as a therapeutic target for treating OC. PCAT‐1 promotes development of OC and represses the chemoresistance of OC to cisplatin, and silencing of PCAT‐1 may be a therapeutic strategy for treating OC.     

Low expression of ENC1 predicts a favorable prognosis in patients with ovarian cancer

Ectodermal-neural cortex 1 (ENC1) belongs to a member of the kelch family of genes. It is an actin-binding protein and plays a pivotal role in neuronal and adipocyte differentiation. Here, we found that lower expression of ENC1 in the ovarian cancer patients was associated with favorable prognosis. In addition, ENC1 was heterogeneously expressed in various ovarian cancer cells. The messenger RNA and protein expression levels of ENC1 in HO-8910PM and NIH:OVCAR-3 cells were obviously higher than that in the other types of ovarian cancer cells. Knockdown of ENC1 in HO-8910PM or NIH:OVCAR-3 cells could significantly increase the reactive oxygen species levels, resulting in inhibition of in vitro proliferation, migration, and invasion. Our findings suggest that decreasing expression of ENC1 may be a new approach that can be used for ovarian cancer treatment.     

LncRNA TP73-AS1 predicts poor prognosis and functions as oncogenic lncRNA in osteosarcoma

TP73 antisense RNA 1 (TP73-AS1), a novel long noncoding RNA (lncRNA), has been suggested to be deregulated in various human cancers and serve as a tumor suppressor or promoter, depending on tumor types. The role of TP73-AS1 in osteosarcoma is still unknown. In our results, TP73-AS1 was highly expressed in osteosarcoma tissue samples and cell lines compared with matching adjacent nontumor tissue specimens and a normal human osteoblast cell line, respectively. Moreover, high expression of TP73-AS1 was statistically associated with advanced Enneking stage, large tumor size, present distant metastasis, and poor histological grade, while exhibiting no statistical association with age, sex, and tumor site. The survival analyses showed that patients with osteosarcoma with high expression of TP73-AS1 obviously had lower overall survival than osteosarcoma patients with low expression of TP73-AS1, and high expression of TP73-AS1 was an independent poor prognostic factor for osteosarcoma patients. The experiments in vitro indicated that inhibition of TP73-AS1 expression depressed osteosarcoma cell viability, migration, and invasion, and arrested cell cycle. In conclusion, TP73-AS1 serves as oncogenic lncRNA participated in osteosarcoma progression.     

A DCS-related lncRNA signature predicts the prognosis and chemotherapeutic response of patients with gastric cancer

The combination of docetaxel, cisplatin, and S-1 (DCS) is a common chemotherapy regimen for patients with gastric cancer (GC). However, studies on long noncoding RNAs (lncRNAs) associated with the chemotherapeutic response to and prognosis after DCS remain lacking. The aim of the present study was to identify DCS mRNAs-lncRNAs associated with chemotherapy response and prognosis in GC patients. In the present study, we identified 548 lncRNAs associated with these 16 mRNAs in the TCGA and {"type":"entrez-geo","attrs":{"text":"GSE31811","term_id":"31811"}}GSE31811 datasets. Eleven lncRNAs were used to construct a prognostic signature by least absolute shrinkage and selection operator (LASSO) regression. A model including the 11 lncRNAs (LINC02532, {"type":"entrez-nucleotide","attrs":{"text":"AC007277.1","term_id":"4580503","term_text":"AC007277.1"}}AC007277.1, AC005324.4, {"type":"entrez-nucleotide","attrs":{"text":"AL512506.1","term_id":"12044702","term_text":"AL512506.1"}}AL512506.1, {"type":"entrez-nucleotide","attrs":{"text":"AC068790.7","term_id":"8571647","term_text":"AC068790.7"}}AC068790.7, {"type":"entrez-nucleotide","attrs":{"text":"AC022509.2","term_id":"6938434","term_text":"AC022509.2"}}AC022509.2, {"type":"entrez-nucleotide","attrs":{"text":"AC113139.1","term_id":"18875234","term_text":"AC113139.1"}}AC113139.1, LINC00106, {"type":"entrez-nucleotide","attrs":{"text":"AC005165.1","term_id":"3242748","term_text":"AC005165.1"}}AC005165.1, MIR100HG, and UBE2R2-AS1) associated with the prognosis of GC was constructed. The signature was validated in the TCGA database, model comparison, and qRT-PCR experiments. The results showed that the risk signature was a more effective prognostic factor for GC patients. Furthermore, the results showed that this model can well predicting chemotherapy drug response and immune infiltration of GC patients. In addition, our experimental results indicated that lower expression levels of LINC00106 and UBE2R2-AS1 predicted worse drug resistance in AGS/DDP cells. The experimental results agreed with the predictions. Furthermore, knockdown of LINC00106 or UBE2R2-AS1 can significantly enhanced the proliferation and migration of GC AGS cells in vitro. In conclusion, a novel DCS therapy-related lncRNA signature may become a new strategy to predict chemotherapy response and prognosis in GC patients. LINC00106 and UBE2R2-AS1 may exhibit a tumor suppressive function in GC.     

lncRNA HCG11 regulates cell progression by targeting miR‐543 and regulating AKT/mTOR pathway in prostate cancer

Prostate cancer (PCa) is a common cancer worldwide, which mostly occurs in males over the age of 50. Accumulating evidence have determined that long non‐coding RNA/microRNA (lncRNA/miRNA) axis plays a critical role in cell progression of cancers, including PCa. However, the pathogenesis of PCa has not been fully indicated. In this study, quantitative real‐time polymerase chain reaction was used to detect the expression of HCG11 and miR‐543. Western blot was applied to measure the protein expression of proliferating cell nuclear antigen, cleavage‐caspase 3 (cle‐caspase 3), N‐cadherin, E‐cadherin, GAPDH, P‐AKT, AKT, p‐mTOR, and mTOR. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT), transwell invasion, and transwell migration assay were used to detect cell proliferation, invasion, and migration, respectively. The function and mechanism of lncRNA HCG11 were confirmed in PCa cell and xenograft mice models. Luciferase assay indicated that miR‐543 was a target miRNA of HCG11. Further investigation revealed that overexpression of HCG11 inhibited cell proliferation, invasion, and migration, whereas induced cell apoptosis by regulating miR‐543 expression in vitro and in vivo. More than that, lncRNA HCG11 inhibited phosphoinositide‐3 kinase/protein kinaseB (PI3K/AKT) signaling pathway to suppress PCa progression. Our data showed the overexpression of HGC11‐inhibited PI3K/AKT signaling pathway by downregulating miR‐543 expression, resulting in the suppression of cell growth in PCa. This finding proved a new regulatory network in PCa and provided a novel therapeutic target of PCa.     

PVT1在恶性肿瘤发生发展中的作用及机制

长链非编码RNA在调节细胞的生长、分化及其他生物学过程中具有重要作用,且与恶性肿瘤等常见疾病密切相关.人类长链非编码RNA PVT1的编码基因由于位于染色体8q24这一脆性位点且临近癌基因MYC而受到广泛关注.浆细胞瘤可变异位基因1(PVT1)在多种肿瘤中高表达,是潜在的癌基因;PVT1也能因染色体断裂重排而与其他基因形成新的融合基因影响恶性肿瘤的表型;PVT1还可与MYC基因相互作用,通过多种途径参与恶性肿瘤细胞的增殖、凋亡等调控.本文对PVT1在恶性肿瘤发生发展中的作用及其机制进行综述.