ADAM17 promotes the invasion of hepatocellular carcinoma via upregulation MMP21
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Cancer Cell International Open Access
PRIMARY RESEARCH
ADAM17 promotes the invasion of hepatocellular carcinoma via upregulation MMP21 Yuqi Xiang1,2†, Liyu Liu1,3†, Ying Wang1,2, Bo Li1,2, Jinwu Peng1,2*† and Deyun Feng1,2*†
Abstract Background: The upregulation of ADAM17 has been reported to be associated with invasion and metastasis in various tumors, however the molecular mechanism of ADAM17 in the progression of hepatocellular carcinoma (HCC) remain to be clarified. Human matrix metalloproteinase 21 (MMP21), the newest member of the MMP gene family, has been suggested to play an important role in embryogenesis and tumor progression. So far, nothing is known about the relationship between ADAM17 and MMP21. Methods: In this study, the expression level of ADAM17 and MMP21 in HCC tissues was measured by immunohistochemistry. The Scratch wounding assay and Transwell were used to identify the invasion and metastasis ability. ELISA was used to evaluate the production of MMP21. Coimmunoprecipitation experiments demonstrated a direct association between ADAM17 and MMP21. HPLC was used to confirmed that ADAM17 participated in the maturation of MMP21. Results: Our present data indicated that ADAM17 and MMP21 was significantly upregulated in human HCC tissues. Knockdown of ADAM17 in HCC inhibited cell invasion and metastasis. Moreover, ADAM17 regulates the secretion and expression of MMP21. Furthermore we discovered a direct association between ADAM17 and MMP21, and we also found MMP21 prodomain could be cleaved by ADAM17. Conclusion: Our data suggest that ADAM17 plays an important role in the development of HCC invasion and metastasis and this function may be implement by MMP21. Keywords: HCC, ADAM17, MMP21, Metastasis Background Hepatocellular carcinoma (HCC) is a highly aggressive and heterogeneous disease. The latest national cancer statistics released by the National Cancer (China) showed that the morbidity of hepatocellular carcinoma is 36.5 per *Correspondence: [email protected]; [email protected] † Yuqi Xiang and Liyu Liu contributed equally to this work † Jinwu Peng and Deyun Feng contributed equally to this work 1 Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China 2 Department of Pathology, Xiangya Basic Medical School, Central South University, Changsha 410008, Hunan, China Full list of author information is available at the end of the article
04 people and that it ranks fourth in malignant tumors 1 [1, 2]. Therefore, we explored the mechanisms underlying the carcinogenesis and progression of HCC to benefit therapy. ADAM17 was initially identified as an important member of the ADAM family by Black RA’s team in 1997. Because the enzyme is responsible for releasing soluble tumor necrosis factor-alpha (TNFα) from the plasmalemma, it is also known as TNFα converting enzyme (TACE/ADAM17) [3]. It has been reported that the dysregulation of ADAM17 contributes to the pathology of various cancers. For instance, ADAM17 protein was highly expressed in esop
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