Progranulin promotes melanoma progression by inhibiting natural killer cell recruitment to the tumor microenvironment.

TitleProgranulin promotes melanoma progression by inhibiting natural killer cell recruitment to the tumor microenvironment.
Publication TypeJournal Article
Year of Publication2019
AuthorsVoshtani R, Song M, Wang H, Li X, Zhang W, Tavallaie MS, Yan W, Sun J, Wei F, Ma X
JournalCancer Lett
Date Published2019 Nov 28
KeywordsAnimals, Cell Line, Tumor, Cell Proliferation, Chemokine CCL5, Disease Progression, Female, Gene Expression Regulation, Neoplastic, Humans, Killer Cells, Natural, Melanoma, Mice, Neoplasm Metastasis, Neoplasm Transplantation, Prognosis, Progranulins, Transcription, Genetic, Tumor Microenvironment, Up-Regulation

Progranulin (PGRN) is a growth factor with significant biological effects in different types of cancer. However, its role in melanoma progression has not been explored. In this study, we first analyze clinical datasets and show that high PGRN expression levels are correlated with poor prognosis of melanoma patients. Further, we demonstrate in a transplanted murine melanoma model in which the endogenous Grn gene encoding PGRN has been deleted that tumor-derived, not host-derived PGRN, promotes melanoma growth and metastasis. Immunological analyses reveal an enhanced infiltration of natural killer cells, but not T lymphocytes, into PGRN-deficient tumors compared to the wild type control. Antibody-mediated depletion confirms the critical role of NK cells in controlling B16 tumor growth. RNA-seq analysis reveals that several chemokines including CCL5 are strongly upregulated in PGRN-deficient tumor. Silencing CCL5 expression in PGRN-deficient tumor reduces NK cell recruitment and restores tumor growth to the control level. Lastly, we show that PGRN inhibits Ccl5 gene expression at the transcriptional level. This study highlights a novel and critical role of PGRN in melanoma growth and metastasis and suggests that it may represent a potential therapeutic target.

Alternate JournalCancer Lett
PubMed ID31491449
PubMed Central IDPMC7519469
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R56 AI095512 / AI / NIAID NIH HHS / United States
R56 AI103157 / AI / NIAID NIH HHS / United States

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