Yang Zhen, Cox James L
Department of Biochemistry, A,T, Still University, 800 W, Jefferson, Kirksville, Missouri 63501, USA.
Cancer Cell Int. 2007 May 8;7:8. doi: 10.1186/1475-2867-7-8.
Most cancers express elevated protease levels which contribute to certain aspects of tumor behavior such as growth, metastatic spread, and angiogenesis. Elevation of the cathepsins of the cysteine protease family correlates with increased invasion of tumor cells. Cysteine proteases such as cathepsins B, H and L type participate in tumor cell invasion as extracellular proteases, yet are enzymes whose exact roles in metastasis are still being elucidated.
We have examined the role of cathepsin L in highly metastatic B16F10 murine melanoma cells through genetic antisense constructs of cathepsin L. The effects of cathepsin L antisense were examined for melanoma cell proliferation, invasion, migration and adhesion.
Antisense expression of cathepsin L, while decreasing enzyme activity in cell lysates, did not influence cell proliferation. Cathepsin L contributed to melanoma cell invasion and also augmented melanoma cell migration. Further, we demonstrated the adhesion of cathepsin L down-regulated clones was unaltered to fibronectin, laminin, and collagen. Finally, the inhibition of melanoma cell migration via down-regulation of cathepsin L appears to be independent of cystatin C expression.
This study shows that cathepsin L facilitates high metastatic B16 melanoma cell invasion and migration. The mechanism of migration inhibition by decreased cathepsin L is independent of cystatin C levels. Since metastasis depends upon both the invasiveness and migration of tumor cells, cathepsin L may be a therapeutic target of strong clinical interest.
大多数癌症中蛋白酶水平升高，这有助于肿瘤行为的某些方面，如生长、转移扩散和血管生成。半胱氨酸蛋白酶家族的组织蛋白酶水平升高与肿瘤细胞侵袭增加相关。诸如组织蛋白酶B、H和L型等半胱氨酸蛋白酶作为细胞外蛋白酶参与肿瘤细胞侵袭，但其在转移中的确切作用仍在阐明之中。
我们通过组织蛋白酶L的基因反义构建体研究了组织蛋白酶L在高转移性B16F10小鼠黑色素瘤细胞中的作用。检测了组织蛋白酶L反义对黑色素瘤细胞增殖、侵袭、迁移和黏附的影响。
组织蛋白酶L的反义表达虽然降低了细胞裂解物中的酶活性，但不影响细胞增殖。组织蛋白酶L促进黑色素瘤细胞侵袭，也增强黑色素瘤细胞迁移。此外，我们证明组织蛋白酶L下调克隆对纤连蛋白、层粘连蛋白和胶原蛋白的黏附未改变。最后，通过下调组织蛋白酶L抑制黑色素瘤细胞迁移似乎与胱抑素C表达无关。
本研究表明组织蛋白酶L促进高转移性B16黑色素瘤细胞的侵袭和迁移。组织蛋白酶L减少导致的迁移抑制机制与胱抑素C水平无关。由于转移取决于肿瘤细胞的侵袭性和迁移，组织蛋白酶L可能是具有强烈临床意义的治疗靶点。
