胰腺癌是消化系统常见恶性肿瘤，国内外发病率均逐年上升，但目前仍缺乏有效治疗手段。我们前期研究发现：(1).清胰化积中药临床治疗胰腺癌具有一定的疗效和优势；(2).基因芯片及样本验证均提示，清胰化积中药在抑制胰腺肿瘤生长同时，谷氨酰胺的主要转运体SLC38A1基因表达量也明显下降；(3).RNAi敲降SLC38A1可显著抑制胰腺癌细胞SW1990的增殖及迁移能力。结合文献报道，我们初步推断清胰化积中药抗胰腺癌作用机制可能与其下调SLC38A1表达进而影响PI3K-Akt信号传导通路有关。本课题拟：1.以SLC38A1为调控靶点，通过体内、外实验进一步探讨氨基酸转运体参与清胰化积方中药抗胰腺癌的作用，以及SLC38A1/PI3K-Akt信号通路作用机制；2.应用分子克隆、微流体芯片及代谢组学技术，探讨清胰化积方在能量代谢中的调控机制，希望为传统中医药治疗胰腺癌、改善预后提供理论基础和实验依据。

Pancreatic cancer incidence has increased dramatically and it has come to the forefront as a public health concern. Tumor metastasis remains a major cause of death for cancer patients. However, prevention and treatment of metastatic disease remains a major challenge to the clinician. During the invasion-metastasis cascade, each event is supported by the cooption of energy metabolism to offer the fuel. Glutamine is the most abundant amino acid in the blood and tissues and has been proved to be essential for tumor growth. As a consequence of progressive tumor growth, host glutamine depletion develops and becomes a hallmark. Solute carrier family 38, member 1（SLC38A1, also known as ATA1）is an important transporter of glutamine and recent studies have found that it's associated with malignant transformation of mammalian cells and tumor progression. Our previous study also found that SLC38A1 which can be regulated by Qingyihuaji Formula could significantly inhibit tumor cell proliferation and migration by RNAi knock down. Based on these findings, it was suggested that Qingyihuaji Formula may play a role in preventing tumorigenesis and tumor progression through the control of glutamine transporter SLC38A1 which could influence the important PI3K-Akt signal pathway. Therefore, we designed this study to investigate influence of SLC38A1 regulation by Qingyihuaji Formula on pancreatic malignant proliferation, apoptosis, invasion and metastasis and its internal mechanism, and also to find out whether it can be a promising molecular target for the prevention and treatment of cancer. we are going to apply molecular cloning to regulate SLC38A1 target genes, then analyze the relationship between gene expression and tumor cells malignant phenotype in vitro and in vivo experiments. We also plan to conduct microfluidic chip (Lab-on-a-chip) and metabolomics study to investigate the mechanism underlying the influence of Qingyihuaji Formula on tumor treatment. We hope our study could offer new insights to the development of new therapeutic strategies against pancreatic cancer.

胰腺癌是一种高度恶性的消化道肿瘤，国内外发病率均逐年上升，依然是临床预后较差的肿瘤之一，目前仍缺乏理想的有效、安全治疗手段。在传统中医辨证论治理论基础上对胰腺癌本质病机进行概括和浓缩，目前认为胰腺癌的病机可能为气机不畅，湿热蕴结，日久成毒，积而成癌，故治宜清热理气,化痰散结。根据该治则而制定的清化积方发挥清热解毒、化湿散结、理气行瘀之功效。前期临床应用中，我们发现以清胰化积为主的中药治疗晚期胰腺癌，具有改善患者生存质量、延长生存期并稳定病灶的优势。基础研究也发现，清胰化积中药对人胰腺癌SW1990具有一定的抑瘤作用，可能与对代谢相关基因的调节相关。在本项课题中，我们分别从mRNA和蛋白水平对清胰化积方治疗后SLC38A1的表达水平进行了验证，结果证实清胰化积方治疗后 SLC38A1 mRNA和蛋白均有明显下降，应用RNAi技术敲降SLC38A1基因表达，结果发现低表达SLC38A1的胰腺癌细胞表现为增殖能力(P<0.0001)、迁移能力显著抑制( 46.7%, P=0.0399)，提示SLC38A1在胰腺癌的发生发展中可能发挥了促癌作用。进而，应用RNA干扰技术成功构建SLC38A1 低表达 SW1990 人胰腺癌细胞系，获得 SLC38A1 高、低表达 SW1990 人胰腺癌细胞，并准备在此基础上进行SLC38A1 对人胰腺癌细胞生物学行为影响的研究。结果发现：调控 SLC38表达对胰腺癌细胞的主要作用表现为增殖和迁移能力的影响，SLC38异常升高导致胰腺癌细胞 PI3K-Akt 信号通路异常，通过对凋亡、增殖、侵袭、血管 生成等下游基因的影响，从而促进胰腺癌细胞的增殖和转移潜能。通过以上对清胰化积方在能量代谢中的调控机制的探讨，有望为传统中医药治疗胰腺癌、改善预后提供理论基础和实验依据。检测SLC表达状态或可用来预测胰腺癌患者对清热化湿中药治疗的疗效，从而筛选清热化湿中药治疗最佳适合人群。