lncRNA HITT inhibits metastasis by attenuating Rab5-mediated endocytosis in lung adenocarcinoma

• Published in: Molecular therapy Vol. 30; no. 3; pp. 1071 - 1088
• Main Authors: Wang, Xingwen, Zheng, Shanliang, Yang, Fan, Zhang, Wenxin, Zhao, Dong, Xue, Xuting, Lin, Qingyu, He, Yunfei, Hu, Guohong, Hu, Ying
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.03.2022; American Society of Gene & Cell Therapy
• Subjects: Adenocarcinoma; cancer metastasis; endocytosis; Endocytosis - genetics; HITT; Humans; Integrin beta1 - genetics; Integrin beta1 - metabolism; Lung - metabolism; Original; Rab5; rab5 GTP-Binding Proteins - genetics; rab5 GTP-Binding Proteins - metabolism; RNA, Long Noncoding - genetics; β1-integrin; HITT; β1-integrin; endocytosis; Rab5; cancer metastasis
• DOI: 10.1016/j.ymthe.2022.01.014
• ISSN: 1525-0016; 1525-0024

Endocytosis of cell surface receptors is essential for cell migration and cancer metastasis. Rab5, a small GTPase of the Rab family, is a key regulator of endosome dynamics and thus cell migration. However, how its activity is regulated still remains to be addressed. Here, we identified a Rab5 inhibitor, a long non-coding RNA, namely HITT (HIF-1α inhibitor at translation level). Our data show that HITT expression is inversely associated with advanced stages and poor prognosis of lung adenocarcinoma patients with area under receiver operating characteristics (ROC) curve (AUC) 0.6473. Further study reveals that both endogenous and exogenous HITT inhibits single-cell migration by repressing β1 integrin endocytosis in lung adenocarcinoma. Mechanistically, HITT is physically associated with Rab5 at switch I via 1248–1347 nt and suppresses β1 integrin endocytosis and subsequent cancer metastasis by interfering with guanine nucleotide exchange factors (GEFs) for Rab5 binding. Collectively, these findings suggest that HITT directly participates in the regulation of Rab5 activity, leading to a decreased integrin internalization and cancer metastasis, which provides important insights into a mechanistic understanding of endocytosis and cancer metastasis. [Display omitted] In this study, we identified a novel mechanism of Rab5 activity regulated by a lncRNA, namely HITT. The newly identified HITT-Rab5 axis plays essential roles in regulating integrin β1 endocytosis, and subsequent cell migration and cancer metastasis, hinting at possible future clinical application.