The cargo protein MAP17 (PDZK1IP1) regulates the immune microenvironment

Abstract

Inflammation is a complex defensive response activated after various harmful stimuli allowing the clearance of damaged cells and initiating healing and regenerative processes. Chronic, or pathological, inflammation is also one of the causes of neoplastic transformation and cancer development. MAP17 is a cargo protein that transports membrane proteins from the endoplasmic reticulum. Therefore, its overexpression may be linked to an excess of membrane proteins that may be recognized as an unwanted signal, triggering local inflammation. Therefore, we analyzed whether its overexpression is related to an inflammatory phenotype. In this work, we found a correlation between MAP17 expression and inflammatory phenotype in tumors and in other inflammatory diseases such as Crohn's disease, Barrett's esophagus, COPD or psoriasis. MAP17 expression correlated also with the markers of inflammation HLAs, BBS10, HERC2, ADNP and PYCARD. Furthermore, we found that MAP17 expression directly regulates NFAT2 and IL-6 activation, inducing the differentiation of monocytes to dendritic cells and suggesting a causal role of MAP17 in inflammation. Immunohistochemistry confirms local inflammation, mainly CD45+ cells, at the site of expression of MAP17, at least in tumors, Crohn's and psoriasis. Therefore, our data indicates that the overexpression of the protein MAP17 plays important role in diseases involving chronic inflammation.

Breast tumor cells promotes the horizontal propagation of EMT, stemness, and metastasis by transferring the MAP17 protein between subsets of neoplastic cells

“…To analyze the possible mechanism by which MAP17 induces changes and EMT in non-transfected cells, especially in light of its previously described role in inflammation 16 , we tested whether conditioned media derived from MAP17-expressing MDA-MB-231 or MDA-MB-468 cells could affect the properties of either parental breast cell line. We found that cells incubated with MAP17-conditioned media exhibited changes in genes connected both to EMT and the acquisition of CSC properties (Fig.…”

“…Conditioned media from transfected MDA-MB-231 and MDA-MB-468 cells were obtained and used as previously described 16 . Non-transfected MDA-MB-231, MDA-MB-468, T-47D, AA, AW, AX, BC, and CE cells were seeded in six-well plates and allowed to grow for 24 hours.…”

“…By packaging different compounds such as RNAs, proteins, lipids, or signaling molecules, they can participate in cell to cell communication 22 , 24 . Meanwhile, MAP17 has been found to increase with tumor stage 1 , 11 , 12 and increased EMT properties 4 , 9 – 11 , being also related to immune attraction to tumor site 8 , 16 . These properties of MAP17 seem to fit well with the reported role for the exosome-dependent adaptations.…”

“…It has also been recently shown that the expression of MAP17 is not restricted to cancer, being also upregulated in chronic inflammatory diseases 16 . In fact, inflammation is a typical event in tumor progression 17 .…”

“…MAP17 expression is correlated with filaggrin, a protein usually downregulated in inflammatory skin diseases, such as atopic dermatitis or psoriasis 18 . Moreover, MAP17 overexpression induces the transcription of genes related to inflammatory response, such as HLAs, IL-6, and NFAT2 8 , 16 . These data suggest that the upregulation of MAP17 is an important event both in cancer and inflammatory diseases.…”