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。

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.