Cystatins comprise a large superfamily of related proteins with diverse biological activities. They were initially characterised as inhibitors of lysosomal cysteine proteases, however, in recent years some alternative functions for cystatins have been proposed. Cystatins possessing inhibitory function are members of three families, family I (stefins), family II (cystatins) and family III (kininogens). Stefin A is often linked to neoplastic changes in epithelium while another family I cystatin, stefin B is supposed to have a specific role in neuredegenerative diseases. Cystatin C, a typical type II cystatin, is expressed in a variety of human tissues and cells. On the other hand, expression of other type II cystatins is more specific. Cystatin F is an endo/lysosome targeted protease inhibitor, selectively expressed in immune cells, suggesting its role in processes related to immune response. Our recent work points on its role in regulation of dendritic cell maturation and in natural killer cells functional inactivation that may enhance tumor survival. Cystatin E/M expression is mainly restricted to the epithelia of the skin which emphasizes its prominent role in cutaneous biology. Here, we review the current knowledge on type I (stefins A and B) and type II cystatins (cystatins C, F and E/M) in pathologies, with particular emphasis on their suppressive vs. promotional function in the tumorigenesis and metastasis. We proposed that an imbalance between cathepsins and cystatins may attenuate immune cell functions and facilitate tumor cell invasion.

Background: Lectins are carbohydrate-binding proteins that exert their activity by binding to specific glycoreceptors. Results: Clitocybe nebularis lectin (CNL) showed biological activity, although its nonsugar-binding and monovalent mutants were inactive. Conclusion:The bivalent carbohydrate-binding property of CNL is essential for its activity. Significance: Understanding the interactions of lectins with glycans and elucidating their modes of action are necessary for their application in biomedicine.

Freshly isolated human primary NK cells induce preferential lysis of Oral Squamous Carcinoma Stem Cells (OSCSCs) when compared to differentiated Oral Squamous Carcinoma Cells (OSCCs), while anti-CD16 antibody and monocytes induce functional split anergy in primary NK cells by decreasing the cytotoxic function of NK cells and increasing the release of IFN-γ. Since NK92 cells have relatively lower levels of cytotoxicity when compared to primary NK cells, and have the ability to increase secretion of regulatory cytokines IL-10 and IL-6, we used these cells as a model of NK cell anergy to identify and to study the upstream regulators of anergy. We demonstrate in this paper that the levels of truncated monomeric cystatin F, which is known to inhibit the functions of cathepsins C and H, is significantly elevated in NK92 cells and in anergized primary NK cells. Furthermore, cystatin F co-localizes with cathepsins C and H in the lysosomal/endosomal vesicles of NK cells. Accordingly, the mature forms of aminopeptidases cathepsins C and H, which regulate the activation of effector granzymes in NK cells, are significantly decreased, whereas the levels of pro-cathepsin C enzyme is increased in anergized NK cells after triggering of the CD16 receptor. In addition, the levels of granzyme B is significantly decreased in anti-CD16mAb and target cell anergized primary NK cells and NK92 cells. Our study provides the cellular and molecular mechanisms by which target cells may utilize to inhibit the cytotoxic function of NK cells.

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