The Role of Matriptase in Cancer

The type II transmembrane serine protease known as matriptase has the potential to mediate the dissolution of extracellular matrix components surrounding tumour cells, catalyse the degradation of intercellular cohesive structures that allows shedding of tumour cells into the extracellular environment, and activate growth and angiogenic factors during tumour progression, and has also recently demonstrated the ability to promote carcinogenesis (142).

Breast cancer cells constitutively activate matriptase and concentrate the activated protease at membrane ruffles, a relocalisation that may convert matriptase from a well-regulated cell junctional protease in mammary epithelial cells to a dysregulated invasion protease at the leading edges of breast cancer cells (143). Thus, matriptase may play an important role in the progression of breast carcinomas. Matriptase is overexpressed in a wide variety of malignant tumours including breast, prostate, ovarian, renal, uterine, colon, oesophageal, epithelial-type meso-thelioma, and cervical cell carcinoma and often correlates with advanced stage clinicopathological parameters (144-154). Studies report that the inhibition of matriptase expression led to suppression of both prostate and ovarian primary tumour growth and metastasis in murine models (108, 112, 155, 156); whereas, overexpression of matriptase-1 was found enhance epidermal tumour formation in transgenic mice (142). It has recently been shown that matriptase also possesses a strong oncogenic potential, as its overexpression in the skin of transgenic mice caused 100% of the mice to develop tumours, 70% of which progressed into carcinomas (142). Importantly, increased expression of HAI-1 completely negated the oncogenic effects of matriptase overexpression (142).

These data strongly suggest that a shift in the balance between matriptase to HAI-1 action causes malignant transformation to occur at a high frequency. There is mounting evidence that demonstrates that an increase in matriptase expression is also accompanied by the concomitant downregulation of HAI-1 expression (26, 144, 146, 157, 158).

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