Targeted inhibition of human collagenase-3 (MMP-13) expression inhibits squamous cell carcinoma growth in vivo
Targeted inhibition of human collagenase-3 (MMP-13) expression inhibits squamous cell carcinoma growth in vivo
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DOI：
10.1038/sj.onc.1207678
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发表时间：
2004-07-01
期刊：
影响因子：
8
通讯作者：
Kähäri, VM
中科院分区：
文献类型：
--
作者：
Ala-aho, R;Ahonen, M;Kähäri, VM
头颈部鳞状细胞癌（SCCs）的特点是局部侵袭和转移到淋巴结的高度倾向。胶原酶-3 （MMP-13）在头颈部SCCs的肿瘤细胞中特异性表达，其表达与其侵袭能力相关。为了专门研究MMP-13在SCC生长和侵袭中的作用，我们构建了一个针对人MMP-13 mRNA的锤头核酶。抗MMP-13核酶在体外有效地裂解MMP-13转录本。腺病毒将抗mmp -13核酶递送到培养的皮肤转移性SCC细胞中，可以有效和特异性地抑制proMMP-13的产生，并通过Matrigel显著抑制SCC细胞的侵袭。此外，腺病毒递送抗MMP-13核酶可促进SCC细胞在72小时内凋亡。将编码抗MMP-13核酶的腺病毒注射到SCID小鼠建立的人SCC异种移植物中，可有效抑制肿瘤生长，抑制MMP-13的表达和明胶溶解活性，并减少肿瘤内增殖细胞的数量。这些结果为MMP-13在SCC生长和侵袭中的重要作用提供了证据，并确定了MMP-13是体内基于核酶治疗SCC的有希望的靶点。
Squamous cell carcinomas (SCCs) of the head and neck are characterized by a high tendency for local invasion and metastasis to lymph nodes. Collagenase-3 (MMP-13) is specifically expressed by tumor cells in SCCs of the head and neck and its expression correlates with their invasion capacity. To specifically examine the role of MMP-13 in the growth and invasion of SCC, we constructed a hammerhead ribozyme targeted against human MMP-13 mRNA. The anti-MMP-13 ribozyme effectively cleaved MMP-13 transcripts in vitro. Adenoviral delivery of the anti-MMP-13 ribozyme to cutaneous metastatic SCC cells in culture resulted in potent and specific inhibition of the production of proMMP-13 and markedly suppressed invasion of SCC cells through Matrigel. In addition, adenoviral delivery of anti-MMP-13 ribozyme promoted apoptosis in SCC cells within 72 h. Intratumoral injection of anti-MMP-13 ribozyme coding adenovirus into human SCC xenografts established in SCID mice potently suppressed tumor growth, inhibited MMP-13 expression and gelatinolytic activity and reduced the number of proliferating cells within the tumors. These results provide evidence for an important role for MMP-13 in SCC growth and invasion and identify MMP-13 as a promising target for ribozyme-based therapy of SCC in vivo.