SLCO4A1转运体调控二氢乳清酸分泌促进乏氧条件下肿瘤细胞存活和增殖的机制研究

肿瘤代谢可以作为抗肿瘤治疗的特异性靶点。乏氧时肿瘤细胞中谷氨酰胺的碳被过度利用生成脂肪酸，但它的氮如何处理以避免氨的积累仍不明确。我们的研究成果表明乏氧条件下谷氨酰胺多余的碳和氮生成二氢乳清酸(DHOA)被安全的排出细胞，但DHOA分泌的分子机制还未探明。申请人前期研究发现：转运体SLCO4A1可以调控DHOA的分泌；乏氧条件下肿瘤细胞的增殖需要SLCO4A1；AMPK/TFE3能够调控SLCO4A1的表达和DHOA分泌。结合文献报道AMPK可以通过激活TFE3进而调控下游基因，因此提出假说：AMPK/TFE3/SLCO4A1信号轴可以调控DHOA分泌以促进乏氧条件下肿瘤细胞的存活和增殖。本项目拟从细胞，动物和临床三个水平利用代谢质谱，同位素示踪和ChIP等技术深入探讨乏氧条件下DHOA分泌的调控机制，解析TFE3与SLCO4A1基因的交互作用，为发掘肿瘤治疗的特异性靶点奠定理论基础。

Tumor metabolism can be used as a specific target for anti-tumor therapy. Under hypoxia, the glutamine-carbon is overused for fatty acids biosynthesis in cancer cells. However, how glutamine nitrogen is disposed to avoid over-accumulating ammonia remains to be determined. Our research results revealed that the excess carbon and nitrogen of glutamine were enriched in dihydroorotate (DHOA) and safely excreted from cells under hypoxia, but the molecular mechanism of DHOA secretion was not revealed. The applicant’s previous research found that the transporter SLCO4A1 can regulate the secretion of DHOA; the proliferation of cancer cells under hypoxia requires SLCO4A1; AMPK/TFE3 can regulate the expression of SLCO4A1 and the secretion of DHOA. Combined with literature reports that AMPK can regulate downstream genes by activating TFE3. It is hypothesized that AMPK/TFE3/SLCO4A1 signal axis can regulate the secretion of DHOA to promote the survival and proliferation of cancer cells under hypoxia. This project intends to use metabolic mass spectrometry, isotope tracing and ChIP techniques to explore the regulation mechanism of DHOA secretion under hypoxia from the cell, animal and clinical levels, and analyze the interaction between TFE3 and SLCO4A1 gene, to lay a theoretical foundation for the discovery of specific targets for tumor therapy.