Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Research Units of Stress and Tumor, Chinese Academy of Medical Sciences, Shanghai, China.
Department of Pathology, Xuzhou Medical University, Xuzhou, China.
RNA Biol. 2021 Nov;18(11):1791-1806. doi: 10.1080/15476286.2020.1871215. Epub 2021 Jan 21.
The adaptation of tumour cells to hypoxic microenvironment is one of the most significant characteristics of many malignant tumour diseases including hepatocarcinoma. Recently, long non-coding RNAs (lncRNAs) have been reported to play important roles in the various levels of gene regulation thus functioning in growth and survival of tumour cells. Here, new hypoxia-related lncRNAs in hepatocarcinoma cells were screened and validated by lncRNA chip-array as well as real-time RT-PCR. Among them, a hypoxia-activated lncRNA that we identified and termed Hypoxia-Activated BNIP3 Overlapping Non-coding RNA (HABON), was not only regulated by hypoxic-induced factor-1α (HIF-1α) but its expression increased significantly under hypoxia in tumour cells. We deciphered the biological characteristics of HABON including its cell localization, genomic location, as well as its full-length sequence, and proved HABON could promote growth, proliferation and clone-formation of hepatocarcinoma cells under hypoxia. Then, we revealed that HABON was transcriptionally activated by HIF-1α in hypoxic cells, furthermore, it could interact with HIF-1α and promote its protein degradation, thus affecting transcription of HIF-1α's target genes to exert its effects on cells. Besides, the elevated expression of HABON under hypoxia could promote the transcriptional activation of BNIP3 through HIF-1α, and increasing the expression level of BNIP3. This research provides a novel clue for the adaptive survival and growth mechanism of tumour under hypoxia, and gives a way to reveal the nature of tumour cells' resistance characteristics to harsh microenvironment.
肿瘤细胞对低氧微环境的适应是许多恶性肿瘤疾病（包括肝癌）的最重要特征之一。最近，长链非编码 RNA（lncRNA）已被报道在基因调控的各个水平发挥重要作用，从而影响肿瘤细胞的生长和存活。在这里，通过 lncRNA 芯片阵列和实时 RT-PCR 筛选并验证了肝癌细胞中的新的与低氧相关的 lncRNA。其中，我们鉴定并命名为低氧激活 BNIP3 重叠非编码 RNA（Hypoxia-Activated BNIP3 Overlapping Non-coding RNA，HABON）的一个低氧激活 lncRNA，不仅受到缺氧诱导因子-1α（Hypoxia-Inducible Factor-1α，HIF-1α）的调控，而且在肿瘤细胞中低氧条件下其表达显著增加。我们解析了 HABON 的生物学特性，包括其细胞定位、基因组位置和全长序列，并证明 HABON 能够在低氧条件下促进肝癌细胞的生长、增殖和克隆形成。然后，我们揭示了 HABON 在低氧细胞中由 HIF-1α转录激活，此外，它可以与 HIF-1α相互作用并促进其蛋白降解，从而影响 HIF-1α靶基因的转录，发挥其对细胞的作用。此外，低氧下 HABON 的表达升高可以通过 HIF-1α促进 BNIP3 的转录激活，增加 BNIP3 的表达水平。本研究为肿瘤在低氧下的适应性生存和生长机制提供了一个新的线索，并为揭示肿瘤细胞对恶劣微环境的抵抗特性的本质提供了一种方法。
