Unknown,Transcriptomics,Genomics,Proteomics

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Comparative proteomic and RNA-seq analyses identify glypican-3 as a hepatocyte host cell receptor for Plasmodium falciparum sporozoite invasion

ABSTRACT: Understanding the liver stage invasion and development of Plasmodium falciparum parasites is difficult due to limitations in current methodologies, namely, a hepatocyte cell line that supports the invasion of sporozoites. In this work we seek to develop and characterize a subclone of the HC-04 cell line that supports higher invasion rates than the parental line. We make use of both RNA-seq and LC-MS/MS proteomics to characterize cells grown in two different mediums. Finally, we identify and validate a surface protein, glypican-3, which is deferentially expressed between parental and subclone cell lines, when compared to HepG2 cells, and demonstrate that antibodies against glypican-3 decrease parasite invasion.

INSTRUMENT(S): Illumina HiSeq 3000

ORGANISM(S): Homo sapiens

SUBMITTER: Rebecca Tweedell

PROVIDER: E-MTAB-6919 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Myeloid-derived suppressor cells (MDSCs) potently suppress the anti-tumor immune responses and also orchestrate the tumor microenvironment that favors tumor angiogenesis and metastasis. The immunosuppressive activity of MDSCs has been extensively investigated, however the molecular networks regulating the non-immunological functions of tumor-expanded MDSCs, are largely unknown. In this study, we identified microRNA-494 (miR-494), whose expression was dramatically induced by tumor-derived factors (TDFs), as an essential player, in regulating the non-immunological activity of MDSCs by targeting PTEN and activating the Akt pathway. TGF-beta 1 was found to be a main tumor-derived factor responsible for the up-regulation of miR-494 in MDSCs. Expression of miR-494 not only enhanced CXCR4-mediated MDSC chemotaxis but also altered the intrinsic apoptotic/survival signal by targeting PTEN, thus contributing to the accumulation of MDSCs in tumor tissues. Consequently, down-regulation of PTEN resulted in increased activity of the Akt pathway and the subsequent up-regulation of matrix metalloproteinases (MMPs) for facilitating tumor cell invasion and metastasis. Knock down of miR-494 significantly reversed the activity of MDSCs and inhibited the tumor growth and metastasis of 4T1 murine breast cancer in vivo. Collectively, our findings reveal that TGF-beta 1-induced miR-494 expression in MDSCs plays a critical role in the molecular events governing the accumulation and non-immunological functions of tumor-expanded MDSCs, and might be identified as a potential target in cancer therapy. BALB/c mice (female, 6- to 8-wk-old) were injected subcutaneously in the mammary fat pad with 100,000 4T1 tumor cells. Three weeks later, tumor-bearing animals were used for the indicated studies. Gr-1+ CD11b+ cells were isolated by immunomagnetic selection from the bone marrow of 4T1 tumor-bearing mice (n=3) and tumor-free BALB/c mice (n=3), then the miRNA expression profile were analyzed using miRCURY LNAM-bM-^DM-" microRNA Arrays.

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Comparative proteomic and RNA-seq analyses identify glypican-3 as a hepatocyte host cell receptor for Plasmodium falciparum sporozoite invasion

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