Up-regulation of long noncoding RNA MINCR promotes non-small cell of lung cancer growth by negatively regulating miR-126/SLC7A5 axis

A growing body of evidence suggests that MYC induced long noncoding RNA (MINCR) is involved in the initiation and progression of various tumors. However, little is known about the biological function and clinical value of MINCR in non-small cell lung cancer (NSCLC). In the present study, results found that MINCR over expression in NSCLC tissue and cell lines was closely related to poor survival in NSCLC. Functional experiments found that decreased MINCR expression inhibits NSCLC cell proliferation and migration and promotes cells apoptosis. Tumor formation assay found that knockdown of MINCR significantly inhibited tumor growth. Results also found that MINCR functions as an oncogene in the metastasis of NSCLC, in part, by acting as a competing endogenous RNA to modulate the miR-126/SLC7A5 axis. Dysfunction of MINCR, miR-126 and SLC7A5 predicted poor prognosis of patients with NSCLC. In conclusion, results suggest that the MINCR-miR-126-SLC7A5 axis plays an important role in the progression of NSCLC and may serve as a potential target for lung cancer diagnosis and treatment.     

Rescue from replication stress during mitosis

Genomic instability is a hallmark of cancer and a common feature of human disorders, characterized by growth defects, neurodegeneration, cancer predisposition, and aging. Recent evidence has shown that DNA replication stress is a major driver of genomic instability and tumorigenesis. Cells can undergo mitosis with under-replicated DNA or unresolved DNA structures, and specific pathways are dedicated to resolving these structures during mitosis, suggesting that mitotic rescue from replication stress (MRRS) is a key process influencing genome stability and cellular homeostasis. Deregulation of MRRS following oncogene activation or loss-of-function of caretaker genes may be the cause of chromosomal aberrations that promote cancer initiation and progression. In this review, we discuss the causes and consequences of replication stress, focusing on its persistence in mitosis as well as the mechanisms and factors involved in its resolution, and the potential impact of incomplete replication or aberrant MRRS on tumorigenesis, aging and disease.     

Telomerase redefined: integrated regulation of hTR and hTERT for telomere maintenance and telomerase activity

Telomerase activity is dependent on the expression of 2 main core component genes, hTERT, which encodes the catalytic component and hTR (also called TERC), which encodes the RNA component. The correlation between telomerase activity and carcinogenesis has made this molecule of great interest in cancer research, however in order to fully understand the regulation of telomerase the mechanisms controlling both telomerase genes need to be studied. Some of these mechanisms of regulation have begun to emerge, however many more remain to be deciphered. For many years hTERT has been regarded as the limiting component of telomerase and much of the research in this field has focussed on its regulation, however it was clear from an early stage that hTR expression was also tightly regulated in normal cells and disease. More recently evidence from biochemistry, promoter studies and mouse models has been steadily increasing for a role for hTR as a limiting and essential component for telomerase activity and telomere maintenance. Perhaps the time has come to redefine our view of telomerase regulation. Knowledge of the mechanisms controlling both telomerase genes in normal systems and cancer may aid our understanding of the role of telomerase in carcinogenesis or highlight potential areas for therapeutic intervention. Here we review the essential requirement of hTR for telomere maintenance and telomerase activity in normal tissues and disease and focus on recent advances in our understanding of hTR regulation in relation to hTERT.     

Molecular profile of breast versus ovarian cancer cells in response to treatment with the anticancer drugs cisplatin, carboplatin, doxorubicin, etoposide and taxol

We assessed changes in the apoptosis-related genes BCL2, BAX, BCL2L12, FAS and CASPASE-3 in OVCAR-3 human ovarian cancer cells and BT-20 human breast cancer cells to provide an insight into the molecular mechanisms involved in the response of these cells to treatment with anticancer drugs and to assess their value as potential biomarkers of chemotherapy response in breast and ovarian cancer. Cells were treated with different chemotherapeutic drugs (cisplatin, carboplatin, doxorubicin, etoposide and taxol) and assessed for changes in the expression of apoptosis-related genes at the mRNA level. Total RNA was extracted, reverse-transcribed into cDNA and amplified by PCR using gene-specific primers. GAPDH was used as a housekeeping gene. Cytotoxicity was assessed by MTT assay. Both cancer cell lines responded differentially at the molecular level to the drug treatments. OVCAR-3 cells showed more pronounced sensitivity and changes compared to BT-20 cells at the mRNA level for different apoptosis-related genes, leading to cell and cancer type dependence in conjunction with drug dependence.     

Cancer and neurodegeneration: between the devil and the deep blue sea

Cancer and neurodegeneration are often thought of as disease mechanisms at opposite ends of a spectrum; one due to enhanced resistance to cell death and the other due to premature cell death. There is now accumulating evidence to link these two disparate processes. An increasing number of genetic studies add weight to epidemiological evidence suggesting that sufferers of a neurodegenerative disorder have a reduced incidence for most cancers, but an increased risk for other cancers. Many of the genes associated with either cancer and/or neurodegeneration play a central role in cell cycle control, DNA repair, and kinase signalling. However, the links between these two families of diseases remain to be proven. In this review, we discuss recent and sometimes as yet incomplete genetic discoveries that highlight the overlap of molecular pathways implicated in cancer and neurodegeneration.     

The spinocerebellar ataxia 8 noncoding RNA causes neurodegeneration and associates with staufen in Drosophila

Spinocerebellar Ataxia 8 (SCA8) appears unique among triplet repeat expansion-induced neurodegenerative diseases because the predicted gene product is a noncoding RNA. Little is currently known about the normal function of SCA8 in neuronal survival or how repeat expansion contributes to neurodegeneration. To investigate the molecular context in which SCA8 operates, we have expressed the human SCA8 noncoding RNA in Drosophila. SCA8 induces late-onset, progressive neurodegeneration in the Drosophila retina. Using this neurodegenerative phenotype as a sensitized background for a genetic modifier screen, we have identified mutations in four genes: staufen, muscle-blind, split ends, and CG3249. All four encode neuronally expressed RNA binding proteins conserved in Drosophila and humans. Although expression of both wild-type and repeat-expanded SCA8 induce neurodegeneration, the strength of interaction with certain modifiers differs between the two SCA8 backgrounds, suggesting that CUG expansions alter associations with specific RNA binding proteins. Our demonstration that SCA8 can recruit Staufen and that the interaction domain maps to the portion of the SCA8 RNA that undergoes repeat expansion in the human disease suggests a specific mechanism for SCA8 function and disease. Genetic modifiers identified in our SCA8-based screens may provide candidates for designing therapeutic interventions to treat this disease.     

TDP-43 regulates cancer-associated microRNAs

Aberrant regulation of miRNA genes contributes to pathogenesis of a wide range of human diseases, including cancer. The TAR DNA binding protein 43 (TDP-43), a RNA/DNA binding protein associated with neurodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs regulated by TDP-43 using RNA-Seq coupled with an siRNA-mediated knockdown approach. TDP-43 knockdown affected the expression of a number of miRNAs. In addition, TDP-43 down-regulation led to alterations in the patterns of different isoforms of miRNAs (isomiRs) and miRNA arm selection, suggesting a previously unknown role of TDP-43 in miRNA processing. A number of TDP-43 associated miRNAs, and their candidate target genes, are associated with human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulating miR-423-3p. In contrast, TDP-43 increases miR-500a-3p expression and binds to the mature miR-500a-3p sequence. Reduced expression of miR-500a-3p is associated with poor survival of lung cancer patients, suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Cancer-associated genes LIF and PAPPA are possible targets of miR-500a-3p. Our work suggests that TDP-43-regulated miRNAs may play multifaceted roles in the pathogenesis of cancer.     

Melatonin regulates cancer migration and stemness and enhances the anti-tumour effect of cisplatin

Melatonin, a lipophilic hormone released from the pineal gland, has oncostatic effects on various types of cancers. However, its cancer treatment potential needs to be improved by deciphering its corresponding mechanisms of action and optimising therapeutic strategy. In the present study, melatonin inhibited gastric cancer cell migration and soft agar colony formation. Magnetic-activated cell sorting was applied to isolate CD133⁺ cancer stem cells. Gene expression analysis showed that melatonin lowered the upregulation of LC3-II expression in CD133⁺ cells compared to CD133⁻ cells. Several long non-coding RNAs and many components in the canonical Wnt signalling pathway were altered in melatonin-treated cells. In addition, knockdown of long non-coding RNA H19 enhanced the expression of pro-apoptotic genes, Bax and Bak, induced by melatonin treatment. Combinatorial treatment with melatonin and cisplatin was investigated to improve the applicability of melatonin as an anticancer therapy. Combinatorial treatment increased the apoptosis rate and induced G0/G1 cell cycle arrest. Melatonin can regulate migration and stemness in gastric cancer cells by modifying many signalling pathways. Combinatorial treatment with melatonin and cisplatin has the potential to improve the therapeutic efficacy of both.     

RNA-driven JAZF1-SUZ12 gene fusion in human endometrial stromal cells

Oncogenic fusion genes as the result of chromosomal rearrangements are important for understanding genome instability in cancer cells and developing useful cancer therapies. To date, the mechanisms that create such oncogenic fusion genes are poorly understood. Previously we reported an unappreciated RNA-driven mechanism in human prostate cells in which the expression of chimeric RNA induces specified gene fusions in a sequence-dependent manner. One fundamental question yet to be addressed is whether such RNA-driven gene fusion mechanism is generalizable, or rather, a special case restricted to prostate cells. In this report, we demonstrated that the expression of designed chimeric RNAs in human endometrial stromal cells leads to the formation of JAZF1-SUZ12, a cancer fusion gene commonly found in low-grade endometrial stromal sarcomas. The process is specified by the sequence of chimeric RNA involved and inhibited by estrogen or progesterone. Furthermore, it is the antisense rather than sense chimeric RNAs that effectively drive JAZF1-SUZ12 gene fusion. The induced fusion gene is validated both at the RNA and the genomic DNA level. The ability of designed chimeric RNAs to drive and recapitulate the formation of JAZF1-SUZ12 gene fusion in endometrial cells represents another independent case of RNA-driven gene fusion, suggesting that RNA-driven genomic recombination is a permissible mechanism in mammalian cells. The results could have fundamental implications in the role of RNA in genome stability, and provide important insight in early disease mechanisms related to the formation of cancer fusion genes.     

Therapeutic genes for cancer gene therapy

Cancer still represents a disease of high incidence and is therefore one major target for gene therapy approaches. Gene therapy for cancer implies that ideally selective tumor cell killing or inhibition of tumor cell growth can be achieved using nucleic acids (DNA and RNA) as the therapeutic agent. Therefore, the majority of cancer gene therapy strategies introduce foreign genes into tumor cells which aim at the immunological recognition and destruction, the direct killing of the target cells or the interference with tumor growth. To achieve this goal for gene therapy of cancer, a broad variety of therapeutic genes are currently under investigation in preclinical and in clinical studies. These genes are of very different origin and of different mechanisms of action, such as human cytokine genes, genes coding for immunstimulatory molecules/antigens, genes encoding bacterial or viral prodrug-activating enzymes (suicide genes), tumor suppressor genes, or multidrug resistance genes.     

环状RNA翻译蛋白在癌症中的研究进展北大核心CSCD

环状RNA(circular RNA,circRNA)是一种单链环状闭合RNA分子,由线性RNA通过反向剪接形成,具有稳定、高度保守、组织特异性等特点。circRNA能够通过形成竞争性内源性RNA、结合蛋白等多种方式参与机体的生理、病理过程。最近发现,circRNA分子可以通过翻译形成多肽或蛋白参与癌症的发生和发展。circRNA是人类癌症中有前途的诊断和预后标志物,也是癌症治疗的潜在药物靶点。本文重点介绍了circRNAs编码的多肽和蛋白质在多种癌症中的相关研究进展。这些多肽和蛋白质分别依赖内部核糖体进入位点和m6A两种不同的机制进行翻译。我们还总结了circRNA编码的多肽和蛋白质在各种癌症的诊断、治疗、预后和机制研究中的潜在用途。     

Regulation of membrane dynamics by Parkinson’s disease-associated genes

Parkinson’s disease (PD), the second most common neurodegenerative disease after Alzheimer’s disease, develops sporadically, and its cause is unknown. However, 5–10% of PD cases are inherited as monogenic diseases, which provides a chance to understand the molecular mechanisms underlying neurodegeneration. Over 20 causative genes have already been identified and are being characterized. These PD-associated genes are broadly classified into two groups: genes involved in mitochondrial functions and genes related to membrane dynamics such as intracellular vesicle transport and the lysosomal pathway. In this review, we summarize the latest findings on the mechanism by which members of the latter group of PD-associated genes regulate membrane dynamics, and we discuss how mutations of these genes lead to dopaminergic neurodegeneration.