Emerging Role Of Hai1 And Hai2 In The Regulation Of Metastasis

The significance of HGF in human cancer metastasis is well established. However, the role of the HAI inhibitors is less clear. The fact that HGF plays such a pivotal role, suggests that the HGF activators (HGFA and matriptase), and HGF activation inhibitors (HAI-1 and HAI-2), are important factors that can influence the metastatic spread of tumours. Recently, a number of studies demonstrate that the ratio between HAI-1/2 and matriptase/HGFA expression is a crucial factor governing the malignant progression of tumour cells in a variety of human cancers including breast, prostate, renal, and colorectal (26, 144, 146, 157, 159, 160). These reports reveal a shift in the balance between HGF activation and inhibition; and demonstrate the malignant progresssion of tumour cells may be a consequence of protease and/or inhibitor dysregulation.

We have shown that both HAI-1 and HAI-2 are downregulated in breast cancer tissues in comparison with normal mammary tissue from a cohort of 120 breast cancer patient samples (26) (Figure 5). In addition we also reveal that HGFA expression is elevated, thus, activation of HGF becomes deregulated and results in enhanced HGF activity. Furthermore, our studies have shown that low levels of HAI expression within breast tumours are associated with a poor prognosis for the breast cancer patient (26). We reveal that HAI-1/2 levels are both significantly reduced in poorly differentiated Grade 3 breast tumour, and that low levels of HAI-1/2 are associated with advanced stage tumours and may possess prognostic value. Several other studies also report that HAI expression inversely correlates with patient prognosis in ovarian, gastrointestinal, glioblastoma, colorectal, and prostate tumours (158, 161-163).

Our most recent studies reinforce the opinion that both HAI-1 and HAI-2 play an important role governing the metastatic nature of tumour cells (160). We employed a ribozyme transgene system to knock down the expression of HAI-1 and HAI-2 in a human breast cancer cell line. Loss of either HAI-1 or HAI-2 resulted in a significantly more aggressive cancer cell phenotype (Figure 6). This study revealed that breast cancer cells with experimentally reduced HAI levels down became dramatically more invasive, and also revealed enhanced motile and proliferative properties. These breast cancer cells expressed such proteolytic enzymes as matriptase, HGFA and hepsin. Therefore, the lack of the HAI-1 or HAI-2 expression leads to dysregulated protease activity, which may subsequently promote cancer progression and metastasis.

Overall, the importance of the HGF regulatory system in cancer metastasis is yet to be fully appreciated. The two Kunitz domains of both HAI-1 and HAI-2 are the key to their inhibitory aspect against a variety of serine proteases. As yet the full list of protease targets for these inhibitors is unclear, however, understanding the interaction of these HAI's with a variety of other serine proteases such as HGFA, matriptase, hepsin, plasma kallikrein, and trypsin will help elucidate the roles and the true value of HAI-1 and HAI-2 in cancer metastasis. We believe that HAI-1 and HAI-2 play a crucial role in breast cancer progression and may have prognostic value. Importantly, an increasing number of studies are suggesting that the HAI inhibitors also display the potential for use in future as anti-cancer agents or biomarkers of cancer progression (26, 98, 157, 158, 160, 163, 164).

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