A natural antisense lncRNA controls breast cancer progression by promoting tumor suppressor gene mRNA stability.
A natural antisense lncRNA controls breast cancer progression by promoting tumor suppressor gene mRNA stability.
复制标题
DOI：
10.1371/journal.pgen.1007802
复制
发表时间：
2018-11
期刊：
影响因子：
4.5
通讯作者：
Prasanth KV
中科院分区：
文献类型：
--
作者：
Jadaliha M;Gholamalamdari O;Tang W;Zhang Y;Petracovici A;Hao Q;Tariq A;Kim TG;Holton SE;Singh DK;Li XL;Freier SM;Ambs S;Bhargava R;Lal A;Prasanth SG;Ma J;Prasanth KV
人类基因组编码数千个长非编码RNA（lncRNA）基因，其中大多数的功能知之甚少。在包括癌症在内的各种疾病中观察到大量lncRNA的异常表达。为了深入了解lncRNA在乳腺癌进展中的作用，我们使用3D细胞培养模型在等基因三阴性乳腺癌（TNBC/基底样）进展细胞系中进行了全基因组转录组分析。我们发现了1853种lncRNA的表达显着改变，其中包括约500种天然反义转录本（NATs）lncRNA。大量的乳腺癌去调节NAT显示与致癌和肿瘤抑制蛋白编码基因顺式共调节表达。对一种这样的NAT，PDCD 4-AS 1 lncRNA的进一步研究表明，它正调控乳腺上皮细胞中肿瘤抑制因子PDCD 4的表达和活性。PDCD 4-AS 1和PDCD 4在TNBC细胞系和患者中均显示表达降低，并且PDCD 4-AS 1的消耗损害了PDCD 4的细胞水平和活性。此外，PDCD 4-AS 1耗尽的TNBC细胞的致瘤特性通过PDCD 4的外源性表达而得到挽救，这意味着PDCD 4-AS 1在PDCD 4的上游起作用。在机制上，PDCD 4-AS 1通过形成RNA双链体来稳定PDCD 4 RNA，并控制PDCD 4 RNA与RNA衰变促进因子如HuR之间的相互作用。我们的研究证明了NAT lncRNA在调节关键致癌基因或肿瘤抑制基因的转录后基因表达中发挥的关键作用，从而有助于TNBC进展。乳腺癌是世界范围内女性最常见的癌症。该疾病的分子机制已得到广泛研究，导致诊断和预后方法的显着改进。尽管生存率总体上有所提高，但每年仍有许多乳腺癌死亡病例报告，提醒我们注意癌症分子生物学时代的潜在知识空白。随着新一代测序技术的发展，大部分基因组被转录为非蛋白质编码RNA（ncRNA），其中包括数千种功能未知的长链ncRNA（lncRNA）。天然反义RNA（NAT）是一组与有义蛋白编码或非编码基因转录方向相反的lncRNA，具有部分或完全互补性。在这篇文章中，我们研究了NAT在乳腺癌进展中的作用，重点是PDCD 4-AS 1的作用，这是一种从已建立的肿瘤抑制基因PDCD 4基因位点表达的NAT。我们观察到PDCD 4-AS 1和PDCD 4在乳腺癌细胞系和患者中显示一致的表达。在乳腺上皮细胞中，PDCD 4-AS 1促进PDCD 4 mRNA的稳定性。PDCD 4-AS 1通过与PDCD 4 RNA形成RNA双链体阻止PDCD 4 RNA与细胞核中RNA衰变因子的相互作用。
The human genome encodes thousands of long noncoding RNA (lncRNA) genes; the function of majority of them is poorly understood. Aberrant expression of a significant number of lncRNAs is observed in various diseases, including cancer. To gain insights into the role of lncRNAs in breast cancer progression, we performed genome-wide transcriptome analyses in an isogenic, triple negative breast cancer (TNBC/basal-like) progression cell lines using a 3D cell culture model. We identified significantly altered expression of 1853 lncRNAs, including ~500 natural antisense transcript (NATs) lncRNAs. A significant number of breast cancer-deregulated NATs displayed co-regulated expression with oncogenic and tumor suppressor protein-coding genes in cis. Further studies on one such NAT, PDCD4-AS1 lncRNA reveal that it positively regulates the expression and activity of the tumor suppressor PDCD4 in mammary epithelial cells. Both PDCD4-AS1 and PDCD4 show reduced expression in TNBC cell lines and in patients, and depletion of PDCD4-AS1 compromised the cellular levels and activity of PDCD4. Further, tumorigenic properties of PDCD4-AS1-depleted TNBC cells were rescued by exogenous expression of PDCD4, implying that PDCD4-AS1 acts upstream of PDCD4. Mechanistically, PDCD4-AS1 stabilizes PDCD4 RNA by forming RNA duplex and controls the interaction between PDCD4 RNA and RNA decay promoting factors such as HuR. Our studies demonstrate crucial roles played by NAT lncRNAs in regulating post-transcriptional gene expression of key oncogenic or tumor suppressor genes, thereby contributing to TNBC progression. Breast cancer is the most common cancer in women worldwide. The molecular mechanisms underlying the disease have been extensively studied, leading to dramatic improvements in diagnostic and prognostic approaches. Despite the overall improvements in survival rate, numerous cases of death by breast cancer are still reported per year, alerting us about the potential gap of knowledge in cancer molecular biology era. The emerging advances in new generation sequencing techniques have revealed that the majority of genome is transcribed into non-protein coding RNAs or ncRNAs, including thousands of long ncRNAs (lncRNAs) of unknown function. Natural antisense RNAs (NATs) constitute a group of lncRNAs that are transcribed in the opposite direction to a sense protein-coding or non-coding gene with partial or complete complementarity. In this manuscript, we investigate the role of NATs in breast cancer progression, focusing on the role of PDCD4-AS1, a NAT expressed from the established tumor suppressor PDCD4 gene locus. We observe that both PDCD4-AS1 and PDCD4 display concordant expression in breast cancer cell lines and patients. In mammary epithelial cells, PDCD4-AS1 promotes the stability of PDCD4 mRNA. PDCD4-AS1 by forming RNA duplex with PDCD4 RNA prevents the interaction between PDCD4 RNA and RNA decay factors in the nucleus.
登录
查看更多内容
影响因子：
56.9
作者：
Carninci, P;Kasukawa, T;Hayashizaki, Y
通讯作者：
Hayashizaki, Y
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
DOI：
10.1073/pnas.96.24.14037
发表时间：
1999-11-23
影响因子：
11.1
作者：
Cmarik, JL;Min, HZ;Colburn, NH
通讯作者：
Colburn, NH
影响因子：
16.6
作者：
Cammas, Anne;Sanchez, Brenda Janice;Lian, Xian Jin;Dormoy-Raclet, Virginie;van der Giessen, Kate;Lopez de Silanes, Isabel;Ma, Jennifer;Wilusz, Carol;Richardson, John;Gorospe, Myriam;Millevoi, Stefania;Giovarelli, Matteo;Gherzi, Roberto;Di Marco, Sergio;Gallouzi, Imed-Eddine
通讯作者：
Gallouzi, Imed-Eddine