The lncRNA HOTAIR: a pleiotropic regulator of epithelial cell plasticity

Abstract

The epithelial-to-mesenchymal transition (EMT) is a trans-differentiation process that endows epithelial cells with mesenchymal properties, including motility and invasion capacity; therefore, its aberrant reactivation in cancerous cells represents a critical step to gain a metastatic phenotype. The EMT is a dynamic program of cell plasticity; many partial EMT states can be, indeed, encountered and the full inverse mesenchymal-to-epithelial transition (MET) appears fundamental to colonize distant secondary sites. The EMT/MET dynamics is granted by a fine modulation of gene expression in response to intrinsic and extrinsic signals. In this complex scenario, long non-coding RNAs (lncRNAs) emerged as critical players. This review specifically focuses on the lncRNA HOTAIR, as a master regulator of epithelial cell plasticity and EMT in tumors. Molecular mechanisms controlling its expression in differentiated as well as trans-differentiated epithelial cells are highlighted here. Moreover, current knowledge about HOTAIR pleiotropic functions in regulation of both gene expression and protein activities are described. Furthermore, the relevance of the specific HOTAIR targeting and the current challenges of exploiting this lncRNA for therapeutic approaches to counteract the EMT are discussed.

The roles of long non-coding RNAs in ovarian cancer: from functions to therapeutic implications

“…EMT refers to the endowment of epithelial cells with mesenchymal feature, allowing tumor cells to leave primary site of the tumor, then invading the paracancerous tissue and migrating to distant organs ( 93 ). Thereby, cancerous mesenchymal cells acquire enhanced motility and ability to invade the surrounding tissues ( 94 , 95 ). Another core character of EMT is that cancer cells are capable of stem cell-like characteristics, allowing tumor cells relentlessly differentiate into numerous tumor cells ( 96 ).…”

Roles of HOTAIR Long Non-coding RNA in Gliomas and Other CNS Disorders

“…Studies indicate that HOTAIR critically influences EMT at multiple levels. Correspondingly, HOTAIR -mediated induction of EMT has been proposed in the pathogeneses of multiple cancers (Amicone et al 2023 ). For instance, transforming growth factor beta 1 (TGF-β1)-induced pathogenic overactivation of HOTAIR robustly triggers EMT in colon cancer cells, and repression of HOTAIR correspondingly results in diminution of EMT and metastatic abilities of these cells (Pádua Alves et al 2013 ).…”

Roles of exosome-derived non-coding RNA in tumor micro-environment and its clinical application

“…肿瘤转移过程涉及细胞微环境的调控及优化肿瘤局部和远距离的生长条件。外泌体非编码RNA主要通过四种方式调控肿瘤的侵袭和转移过程。第一种方式：侵袭性较小的肿瘤细胞可以通过肿瘤来源的外泌体吸收从侵袭性肿瘤细胞传递的非编码RNA，这可能会促使原发性肿瘤恶化。例如，转移性乳腺癌可能通过原发性肿瘤将外泌体miR-10b释放到周围正常细胞的培养环境中来促进细胞侵袭 ［ 21 ］ 。第二种方式：原发性肿瘤细胞通过肿瘤微环境中的外泌体非编码RNA与肿瘤微环境中的其他非肿瘤细胞进行通信，间接调控肿瘤的侵袭和转移。例如，转移性乳腺癌细胞表达和分泌的miR-105能够通过下调紧密连接并破坏内皮单层的屏障功能诱导血管通透性并促进转移 ［ 22 ］ 。第三种方式：外泌体非编码RNA可通过激活或抑制某些信号诱导的EMT过程来促进肿瘤细胞的侵袭。EMT在调控肿瘤侵袭的过程中有着重要意义，即上皮样肿瘤细胞失去极性和黏附特性，赋予迁移和侵袭特性，并成为间质样细胞。研究发现，外泌体lncRNA HOTAIR在膀胱癌患者中高表达，并通过诱导EMT过程以激发肿瘤的侵袭性；大多数miRNA都具有明显的促进EMT的作用 ［ 23 ］ 。同时，外泌体中的一些miRNA的表达与EMT程度相关，例如肿瘤源性外泌体miR-375-3p能够通过抑制E-cadherin和ZEB1并靶向YAP1抑制EMT进程 ［ 24 - 25 ］ 。外泌体miRNA还可以通过诱导巨噬细胞M2极化增强EMT，例如miR-253p、miR-130b-3p、miR-425-5p ［ 26 ］ 。circRNA可以通过捕获miRNA在肿瘤中充当竞争性内源RNA，例如外泌体circ_0001359通过捕获miR-582-3p并促进大鼠前列腺上皮细胞系-1细胞中的EMT来激活TGF-β信号通路 ［ 27 ］ 。第四种方式：外泌体非编码RNA通过靶向其他促进或抑制肿瘤的分子或细胞调控肿瘤的侵袭和转移。例如，肺腺癌细胞可以通过外泌体将miR-19b-3p转运到肿瘤相关巨噬细胞并促进M2极化，M2极化的肿瘤相关巨噬细胞可以通过外泌体将LINC00273转运到肺腺癌细胞中，抑制Hippo信号通路并激活YAP信号通路，促进miR-19b-3p被包装到肺腺癌细胞分泌的外泌体中，从而增强肺腺癌细胞的侵袭和迁移能力，促进肿瘤转移 ［ 28 ］ 。…”