MANF是一新型神经营养因子，内质网应激上调其表达与分泌，但它与肿瘤的关系未见报道。我们在筛选与MANF相互作用的蛋白时，发现MANF可与p65（NF-kB的一个亚单位）相互作用，而后者与肿瘤的发生密切关系，提示MANF可能参与了肿瘤的调控。我们的前期研究也发现，MANF的表达水平与肝细胞癌（HCC）患者的存活有关，推测MANF可能是一个抑癌因子，通过与p65的相互作用来抑制肿瘤的发生发展。为此，我们拟在200例HCC中检测MANF的表达，并比较与血清中MANF的水平是否一致，以此评估MANF是否可以作为血清学诊断指标；在肝癌细胞株上通过过表达和敲低MANF来证明MANF对肝癌细胞恶性生物学行为的抑制；在肝脏特异性敲除MANF基因的小鼠模型上，用化学剂诱导肝癌，通过与野生型小鼠肿瘤诱导时间和程度的比较，来验证MANF的抑癌作用；从MANF对NF-kB信号通路的调节来探讨MANF的抑癌机制。

MANF is a new neurotrophic factor. ER stress up-regulates MANF expression and secretion. However, whether MANF play a role in carcinogenesis is unknown. On screening the proteins interacting with MANF by using of yeast two-hybrid assay, we found MANF directly interacts with p65 (a subunit of NF-kB). It was well known NF-kB pathway is involved in carcinogenesis. Therefore, it is reasonable to assume that MANF may be associated with carcinogenesis. To test it, we detected the cancer tissues from 150 pateints by using of immunohistochemistry assay. We found that the level of MANF was reduced in the hepatocelluler cancer (HCC) in large part of patients（74.7%）. In small number of patients with high MANF level, the rate of survival was significantly increased, compared with the control (p=0.022). This result suggests that MANF probably is a tumor suppressor, and MANF may inhibit carcinogenesis and development by regulating NF-kB pathway. To prove the hypothesis, we firstly detect the levels of MANF in liver tissues and serum of 200 patients by using immunohistochemistry and ELISA, respectively. The change trends of MANF were compared in the liver tissues and serum. Based on this result, we will figure out whether MANF becomes a serum biomarker. Secondly, we will investigate the effects of MANF on the carcinogenesis and the malignant biological behavior, including migration, invasion, and metastasis in hepatoma cell lines. Thirdly, we will verify the tumor suppressive effect of MANF in the specific liver MANF knockout mice. In the MANF knockout mice, liver cancer was induced by diethylnitrosamine and CCl4. Finally, we will explore the mechanisms by which MANF suppresses the carcinogenesis and development via interacting with p65. This study will find a new tumor suppressor and discover a novel mechanism in liver carcinogenesis.