Objective To investigate the role of Annexin A7(ANXA7) in the development of HCC by analyzing ANXA7 expression in hepatocarcinogenesis and identifying its potential interaction molecule. Methods NXA7 mRNA expression was analyzed by real-time PCR in 48 HCC tissues and tumor adjacent tissues, and different hepatic cancer tissues and cell lines. To analyze the effect of ANXA7 on hepatoma proliferation, ANXA7 was overexpressed or inhibited by specific siRNA in hepatic cancer cells. Co-immunopricipitation (co-IP) method was used to detect the specific binding protein of ANXA7 in HCC cells. The key sites of protein interaction were analyzed by point mutation. Western blotting analysis was used to study the effect of ANXA7 on IGFBP2 activated ERK1/2 phosphorylation. Results The expression of ANXA7 was down-regulated in both hepatoma tissue samples and hepatoma cell lines. Insulin-like growth factors binding protein 2 (IGFBP2) could specifically bind with ANXA7 through the key RGD site. Up-regulated expression of ANXA7 could inhibit the proliferation of tumor cells (P<0.05) and decrease the phosphorylation of ERK1/2. Accordingly, down-regulated expression of ANXA7 could enhance the proliferation of tumor cells (P<0.01) and increase phosphorylation of ERK1/2 in HCC cells. Conclusion ANXA7 may serve as a potential tumor suppressive molecule, participating in the regulation of IGFBP2-activated ERK1/2 phosphorylation and affecting the proliferation of hepatoma cells.