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The SERPINA5 was reported to be deregulated in renal, breast, prostate and ovarian cancers. However, the roles of SERPINA5 in cancer remain greatly elusive. In this study, we found that the DNA dosage and expression level of the SERPINA5 gene were significantly decreased in HCC by quantitative real\u2010time PCR. Notably, the expression levels of SERPINA5 negatively correlated with malignant progression of HCC. The SERPINA5 gene was further observed to reduce in\u00a0vitro and in\u00a0vivo metastatic potential of HCC cells. Moreover, secreted SERPINA5 protein also could inhibit the metastatic ability of HCC cells. Finally, we discovered that one of the mechanisms explaining SERPINA5 inhibition of HCC metastasis is through direct interaction with fibronectin and disruption of the fibronectin\u2013integrin signaling pathway. 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