Abstract
The multistructural and multifunctional transmembrane glycoprotein CD44 is overexpressed in many tumors of distinct origin including malignant melanoma and contributes to a poor prognosis by affecting cell proliferation, cell migration, and also the sensitivity for apoptosis induction. Previous studies reported so far 15 CD44 regulatory microRNAs (miRs) in different cell systems.Using a novel method for miR affinity purification miR-143-3p was identified as most potent binder to the 3’ untranslated region (UTR) of CD44. Overexpression of miR-143-3p in melanoma cells inhibits CD44 translation, which is accompanied by a reduced proliferation, migration and enhanced daunorubicin induced apoptosis of melanoma cells in vitro.Analyses of discordant CD44 and miR-143-3p expression levels in human melanocytic nevi and dermal melanoma samples demonstrated medium to high CD44 levels with no association to tumor grading or staging. The CD44 expression correlated to PD-L1, but not to MART-1 expression in malignant melanoma. Interestingly, the CD44 expression was inversely correlated to the infiltration of pro-inflammatory immune effector cells.In conclusion, the tumor suppressive miR-143-3p was identified as the most potent CD44 inhibitory miR, which affects growth characteristics of melanoma cells suggesting the implementation of miR-143-3p as as a potential anti-CD44 therapy of malignant melanoma.
Highlights
The transmembrane glycoprotein CD44 isoform (CD44s) is constitutively expressed on embryonic stem cells, in connective tissues and in the bone marrow and overexpressed in different tumor entities as well as in cancer stem cells (CSC)
The tumor suppressive miR-143-3p was identified as the most potent CD44 inhibitory miR, which affects growth characteristics of melanoma cells suggesting the implementation of miR-143-3p as as a potential anti-CD44 therapy of malignant melanoma
Despite more than 15 CD44 regulatory miRs have been reported in the literature (Table 1)
Summary
The transmembrane glycoprotein CD44 is constitutively expressed on embryonic stem cells, in connective tissues and in the bone marrow and overexpressed in different tumor entities as well as in cancer stem cells (CSC). The human CD44 gene is highly conserved, localized on the short arm of chromosome 11 and encoded by 20 exons, from which 10 are constant in all isoforms [7]. The “standard” CD44 isoform (CD44s) encoded by www.oncotarget.com the 10 constant exons has a molecular weight of 85–90 kDa and is ubiquitously expressed in vertebrates. In contrast to CD44s, the distribution of CD44v isoforms is restricted to selected epithelial, proliferating and even tumor cells [2, 10, 11]
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