ABSTRACT

Mouse and rats are staple model organisms that have been traditionally used for oncological studies; however, their short lifespan and highly prone to cancers limit their utilizationsin understanding the mechanisms of cancer resistance. In recent years, several studies of the non-standard long-lived mammalian species like naked mole rat (NMR) have provided new insights of mechanisms in natural anti-cancer. How long-lived species genetically maintain longevity and cancer-resistance remains largely elusive. To better understand the underlying anti-cancer mechanisms in long-lived mammals, we genome widely identified long noncoding RNA (lncRNA) transcripts of two longevous mammals, bowhead whale (BW, Balaena mysticetus) and Brandt’s bat (BB, Myotis brandtii) and featured their sequence traits, expression patterns, and their correlations with cancer-resistance. Similar with naked mole rat (NMR, Heterocephalus glaber), the most long-lived rodent, BW and BB lncRNAs show low sequence conservation and dynamic expressions among tissues and physiological stages. By utilizing k-mers clustering, 75–136 of BW, BB and NMR lncRNAs were found in close relation (Pearson’s r ≥0.9, p < 0.01) with human ageing diseases related lncRNAs (HAR-Lncs). In addition, we observed thousands of BB and BW lncRNAs strongly co-expressed (r > 0.8 or r <-0.8, p < 0.01) with potential tumour suppressors, indicating that lncRNAs are potentially involved in anti-cancer regulation in long-lived mammals. Our study provides the basis for lncRNA researches in perspectives of evolution and anti-cancer studies.

Abbreviations: BW: bowhead whale; BB: Brandt’s bat; NMR: naked mole rat; LLM: long-lived mammal; HTS: human tumour-suppressors; PTS: potential tumour suppressor; ARD: ageing related diseases; HAR-Lncs: lncRNAs that related with human ageing diseases; Kmer-lncs: lncRNAs in long-lived mammal species that corelated (Pearson’sr ≥0.9, p < 0.01) with the 10 HAR-Lncs by k-mers clustering; All-lncs: all the lncRNAs in long-lived mammal species; SDE-lncs: significant differentially expressed lncRNAs

摘要

小鼠和大鼠是传统上用于肿瘤学研究的主要模式生物；然而，它们的寿命短且极易患癌症，这限制了它们在了解抗癌机制方面的应用。近年来，对裸鼹鼠 (NMR) 等非标准长寿哺乳动物物种的多项研究为天然抗癌机制提供了新见解。长寿物种如何在遗传上保持长寿和抗癌能力仍然难以捉摸。为了更好地了解长寿哺乳动物的潜在抗癌机制，我们对两种长寿哺乳动物、弓头鲸（BW，Balaena mysticetus）和布兰特蝙蝠（BB，Myotis brandtii）的长非编码 RNA (lncRNA) 转录本进行了基因组广泛鉴定。) 并展示了它们的序列特征、表达模式以及它们与抗癌性的相关性。与裸鼹鼠（NMR，Heterocephalus glaber）类似，寿命最长的啮齿动物，BW 和 BB lncRNA 在组织和生理阶段表现出低序列保守性和动态表达。通过使用 k-mers 聚类，发现 75-136 个 BW、BB 和 NMR lncRNA与人类衰老疾病相关的 lncRNA（HAR-Lncs）密切相关（Pearson r ≥0.9，p < 0.01）。此外，我们观察到数以千计的 BB 和 BW lncRNAs 强烈共表达（r > 0.8 或r<-0.8, p < 0.01) 具有潜在的肿瘤抑制因子，表明 lncRNA 可能参与长寿哺乳动物的抗癌调节。我们的研究从进化和抗癌研究的角度为lncRNA研究提供了基础。

缩写： BW：弓头鲸；BB：布兰特的球棒；NMR：裸鼹鼠；LLM：长寿哺乳动物；HTS：人类肿瘤抑制剂；PTS：潜在的肿瘤抑制因子；ARD：衰老相关疾病；HAR-Lncs：与人类衰老疾病相关的lncRNA；Kmer-lncs：长寿哺乳动物物种中的 lncRNA，通过 k-mers 聚类与 10 个 HAR-Lnc相关（Pearson r ≥ 0.9，p < 0.01）；All-lncs：长寿哺乳动物物种中的所有lncRNA；SDE-lncs：显着差异表达的 lncRNA