葡萄糖缺乏诱导的长链非编码RNA-GDLR促进肝癌细胞存活和增殖的作用及机制研究

It has been recognized for a long time that compared to their normal cell counterparts, tumor cells exhibit a unique metabolism referred to as the Warburg effect, resulting in enhanced glucose uptake to supply energetic and biosynthetic pathways. However, within solid tumors, nutrients such as glucose are normally limited. This glucose-limited/deprived environment requires that tumor cells exhibit metabolic flexibility to sustain their survival, however, the underlying mechanisms remain uncertain. More specifically, it is still unknown whether long non-coding RNA (lncRNA) promotes cancer cell survival under glucose-deprived condition. Our research aims to address this issue. Our preliminary data suggest that under glucose-deprived condition, ATF4 transcriptionally up-regulates expression of lncRNA-GDLR (Glucose Deprivation-induced Long non-coding RNA). GDLR interacts with PHGDH, the rate-limiting enzyme in de novo serine biosynthesis, and promotes GSH production and decreases ROS levels, thereby promoting liver cancer cell survival under glucose-deprived condition. In addition, GDLR is able to promote liver cancer cell proliferation. In this study, we will further investigate the molecular mechanism whereby glucose deprivation-induced GDLR promotes liver cancer survival and proliferation. We will also evaluate the possible role of GDLR in the development of liver cancer. This study will generate novel insights into the mechanisms of how cancer cells sustain growth and survival under glucose-deprived environment. This may also implicate GDLR as a new potential therapeutic target for the treatment of cancer.

与正常细胞相比，肿瘤细胞会因为发生代谢重编程而消耗更多的葡萄糖以维持其快速生长。然而实体肿瘤在生长的过程中通常会面临营养压力如葡萄糖缺乏的情况，为了应对葡萄糖缺乏这一微环境，肿瘤细胞必须做出相应改变，但是具体的分子基础仍不明确，特别是长链非编码RNA是否能在葡萄糖缺乏微环境下促进肿瘤细胞的存活并不清楚。我们的前期研究结果提示，在葡萄糖缺乏条件下，肝癌细胞通过ATF4转录上调长链非编码RNA-GDLR的表达，GDLR能够结合丝氨酸合成的关键限速酶PHGDH，并促进GSH的生成及降低ROS水平，进而促进肝癌细胞的存活；同时，GDLR也具有促进肝癌细胞增殖的功能。本项目将在已有的工作基础上，进一步深入研究葡萄糖缺乏诱导的GDLR促进肝癌细胞存活和增殖的作用及机制；也将研究其在肝癌形成中的作用。这将有助于人们更加清晰地认识肿瘤细胞如何应对葡萄糖缺乏这一肿瘤微环境，并可能为肿瘤治疗提供新的潜在靶点。

与正常细胞相比，肿瘤细胞会因为发生代谢重编程而消耗更多的葡萄糖以维持其快速生长。然而实体肿瘤在生长的过程中通常会面临营养压力如葡萄糖缺乏的状况，为了应对葡萄糖缺乏这一微环境，肿瘤细胞必须做出相应改变，但是具体的分子基础仍不明确，特别是长链非编码RNA是否能在葡萄糖缺乏微环境下促进肿瘤细胞的存活并不清楚。本项目以此为切入点，我们的研究鉴定了一个新的响应葡萄糖缺乏状态的长链非编码RNA-linc01564；发现转录因子ATF4在葡萄糖缺乏诱导linc01564表达的过程中发挥了重要的介导作用。linc01564能够激活丝氨酸合成通路，并促进GSH的生成及降低ROS水平，最终促进葡萄糖缺乏条件下肝癌细胞的存活和增殖。在分子机制上，linc01564能够通过miR-107/103a-3p上调丝氨酸合成的关键限速酶PHGDH的表达水平。另外，linc01564在肝细胞癌中呈现高表达的状态，并且其表达水平与肝癌病人的预后呈负相关。这些研究结果从长链非编码RNA的角度揭示了肝癌细胞如何响应其所处的能量应激的微环境，并暗示linc01564可能是干预肝癌的一个潜在靶点。在本项目的大力资助下，项目负责人以通讯作者的身份在PNAS、Oncogene和EMBO Reports等国际主流期刊上发表SCI学术论文5篇。

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