食管癌是一种常见的消化系统恶性肿瘤，是全球癌症相关死亡的第六大原因1。尽管近年来研究人员发现基因突变改变食管癌的易感性，表观遗传变化有助于食管癌的发展2-3，但驱动食管癌发生的详细机制仍未阐明。因此，揭示食管癌的分子机制有望推动新的诊断和治疗策略的发展。
Esophageal cancer (ESCA), a common digestive system malignancy, is the sixth leading cause of cancer-related death worldwide1. Although researchers have discovered in recent years that genetic mutations alter susceptibility to ESCA and that epigenetic changes contribute to the development of ESCA2-3, the detailed mechanisms that drive the tumorigenesis of ESCA are still not well understood. Therefore, uncovering the molecular mechanism of ESCA is expected to contribute to the development of new diagnostic and therapeutic strategies.
2023年03月13日，郑州大学附属郑州中心医院曹巍教授团队在Gene & Protein in Disease（GPD）杂志上发表了最新研究成果“Alkylation repair homolog 3-regulated esophageal squamous cell carcinoma associated long non-coding RNA 1 is required for maintaining the stemness of esophageal cancer”。该研究揭示了ESCCAL-1转录后修饰在食管癌干性维持中的作用，为开展食管癌的分子治疗研究提供参考依据。
March 13, 2023,CaoWei, a professor at Zhengzhou Central HospitalAffiliated toZhengzhou University, and his team published their latest findings in the journal Gene & Protein in Diseaseentitled“Alkylation repair homolog 3-regulated esophageal squamous cell carcinoma associated with long non-coding RNA 1 is required for maintaining the stemness of esophageal cancer”.This study revealed the role of ESCCAL-1 post-transcriptional modification instemnessmaintenance ofESCA, and provided reference for molecular therapy ofESCA.
长链非编码RNA（Long non-coding RNAs, LncRNAs）是一种长度超过200个核苷酸的非编码转录物，广泛介导肿瘤发展并影响疾病预后。我们之前发现ESCCAL-1是ESCA中的关键致癌LncRNA。然而，ESCCAL-1在ESCA中表达失调的机制仍未完全了解。N1 -甲基腺苷（m1A）甲基化是真核细胞最常见的RNA修饰之一。去甲基化酶通过影响转录本的m1A修饰来调控RNA稳定性、剪接、翻译和其他过程。RNA m1A修饰在转录后水平控制细胞内基因表达谱，并参与调控肿瘤起始和发展4-5。但m1A修饰在ESCA中的作用及其对LncRNA的表达调控尚不清楚。
Long non-codingRNAs(LncRNAs),non-codingtranscripts longerthan200 nucleotides,widelymediatetumordevelopmentandinfluencediseaseprognosis.We previouslyfoundthatESCCAL-1isacriticaloncogenicLncRNAin ESCA.However, themechanismresponsible for the uncontrolled expression of ESCCAL-1 inESCAremainsto befully understood. N1-methyladenosine (m1A)methylation is one ofthe eukaryotic cell’smost common RNA modifications.Deregulated methylase regulates RNA stability, splicing, translation,and other processes by affectingthem1A modificationof transcripts.RNA m1A modificationcontrols intracellular gene expression profile at the post-transcriptional leveland participates in the regulation of tumorinitiationand development4-5. However, the function of m1A modification inESCAand its regulation ofLncRNA expression remain unclear.
在本研究中，我们发现ESCCAL-1的高表达与ESCA的进展和预后密切相关。ESCCAL-1的缺失抑制了ESCA的干细胞样特性，ESCCAL-1的过表达促进了ESCA的自我更新能力。ALKBH3是一种RNA去甲基酶，它可以清除ESCCAL-1的m1A修饰，并导致后者在ESCA中表达上调。ALKBH3/ESCCAL-1信号轴参与ESCA干性维持。本研究拓展了LncRNA转录后修饰在癌症发展中的认识，并为ESCA提供了新的治疗靶点。
In this study,we found that high expression of ESCCAL-1 was closely related to the progression and prognosis ofESCA.The absence of ESCCAL-1 inhibits the stem-like properties ofESCA cells, and the forced expression of ESCCAL-1 promotes the self-renewal ability ofESCA.ALKBH3, an RNA demethylase, erases the m1A modification of ESCCAL-1 and causes the up-regulation of the latter expression inESCA.ALKBH3/ESCCAL-1 axis is involved in thestemnessmaintenance ofESCA. This studyexpands the understanding ofLncRNApost-transcriptional modificationin cancer development, andprovidea new therapeutic target forESCA.
该研究由郑州大学附属郑州中心医院曹巍教授课题组完成，曹巍教授为论文的通讯作者，崔渊博博士为论文的第一作者。本研究工作获得河南省医学科研基金（LHGJ20200765，SB201903032，SBGJ202003053）多个项目资助。
Thisstudy was carried out by Prof.Cao’s teamof Zhengzhou Central Hospital Affiliated to Zhengzhou University.Prof.Caois the corresponding author of the paper, andDr.Cuiis the first author.This work was supported by several projects of Henan Medical Research Foundation（LHGJ20200765, SB201903032, SBGJ202003053）.
参考文献：
1.SiegelRL,et al.Cancer statistics, 2020. CA Cancer J Clin,2020,70(1):7-30.
2.Cui Y,et al. Whole-genome sequencing of 508 patients identifies key molecular features associated with poor prognosis in esophageal squamous cell carcinoma. Cell Res,2020,30(10):902-913.
3.Xi Y,et al. Multi-omic characterization of genome-wide abnormal DNA methylation reveals diagnostic and prognostic markers for esophageal squamous-cell carcinoma. Signal Transduct Target Ther,2022,7(1):53.
4.Wu Y,et al. RNA m1A methylation regulates glycolysis of cancer cells through modulating ATP5D. Proc Natl Acad Sci U S A,2022,119(28):e2119038119.
5.Lu Q,et al. LncRNA ALKBH3-AS1 enhances ALKBH3 mRNA stability to promote hepatocellular carcinoma cell proliferation and invasion. J Cell Mol Med, 2022, 26(20):5292-5302.
文章链接：
https://accscience.com/journal/GPD/2/1/10.36922/gpd.30
