谷丙转氨酶GPT2通过HIF1α促进乳腺癌转移的机制研究

Increased glutamine metabolism is a hallmark of cancer. Mitochondrial glutamic pyruvate transaminase (GPT2) catalyzes the reversible transamination between alanine and α-ketoglutarate (α-KG) to generate pyruvate and glutamate during cellular glutamine catabolism. GPT2 can promote tumorigenesis of breast cancer cells. Matrix metalloproteinase 2 (MMP2) has been proved to promote tumor metastasis and to correlate with adverse prognosis in various tumors. Functional study revealed that GPT2 promoted the migration and metastasis of breast cancer cells, and increased the protein level of HIF1α and expression of MMP2. Based on these discoveries，the project aims to: (1) clarify the regulation effect of GPT2 on intracellular HIF1αin cancer metastasis; (2) explore the mechanism of MMP2 activation by GPT2 through HIF1α; (3) validate how MMP2 promotes breast caner metastasis. Eventually we will demonstrate the mechanism underlying GPT2 that promotes metastasis of breast cancer by regulating HIF1α which probably activated MMP2 in promoting the metastasis. The successful implementation of this project provides novel target and ideas for diagnosis and treatment for breast cancer metastasis.

谷氨酰胺代谢是癌症的一个重要标志。谷丙转氨酶2(GPT2)是谷氨酰胺代谢的重要催化酶，主要催化α-酮戊二酸（α-KG）和谷氨酸之间的可逆反应，能够增强乳腺癌细胞的致瘤性。基质金属蛋白酶（MMP2）能促进肿瘤转移并导致多种肿瘤的不良预后。我们发现GPT2能够促进乳腺癌细胞的转移，增加HIF1α的蛋白水平，并上调MMP2的表达。基于此，本项目拟开展如下研究：（1）确认GPT2对HIF1α的调节参与了对乳腺癌的促转移作用；（2）探明GPT2通过HIF1α调节MMP2的机制；（3）阐明GPT2通过MMP2促进乳腺癌转移的作用和途径。最终我们将明确GPT2通过调节HIF1α增加了MMP2的表达，进而促进了乳腺癌的转移。本项目的顺利实施将为乳腺癌转移的诊治提供新的思路。

谷丙转氨酶2(GPT2)是谷氨酰胺代谢的重要催化酶，而谷氨酰胺代谢是癌症的一个重要标志。前期研究发现，GPT2在临床乳腺癌样本中表达增加，并且能够促进乳腺癌细胞的转移，增加HIF1α的蛋白水平，上调MMP2的表达，但其机制并不清楚。本项目在上述研究背景的基础上证实：（1）MMP2在临床乳腺癌样本中表达增加并且促进乳腺癌的转移；（2）GPT2对HIF1α的调节参与了对乳腺癌的促转移作用；（3）GPT2通过HIF1α增加MMP2进而促进乳腺癌转移。本项目揭示了GPT2通过降低乳腺癌中α-KG的含量，增加HIF1α的蛋白稳定性，进而增加MMP2的表达促进乳腺癌转移的作用机制，为研发新的靶向性乳腺癌转移治疗手段奠定实验及理论基础。