PRL3-zumab as an immunotherapy to inhibit tumors expressing PRL3 oncoprotein.
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ABSTRACT:
SUBMITTER: Thura M
PROVIDER: S-EPMC6554295 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We report the use of 4sU-seq to determine the role of PRL3 in transcriptional processivity in human melanoma cells overexpressing either PRL3 or empty vector control. Genome-wide analysis of read coverage across length of equalised genes revealed a distinct accumulation of transcripts towards the 5’ end in PRL3 overexpressing cells. Furthermore, we identify the genes that were enriched with 5’ transcripts in the PRL3 expressing cells by comparing the intronic read counts (normalized for length) at the 5’ and 3’ end of the gene and termed this metric the transcriptional processivity ratio (TPR). Comparing the TPRs for each gene between control cells and cells expressing PRL3, we found 1745 genes that were enriched for transcripts at the 5’ end and 40 genes that were enriched at the 3’ end in the PRL3 expressing melanoma cells compared with controls. Over 62% of the genes with altered TPRs showed a significantly altered change in total RNA differential expression analysis between PRL3 cells and control cells. These data illustrate a function for PRL3 in the regulation of transcriptional processivity that is enough to substantially alter steady-state mRNA levels.
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Project description:PRL3, a unique oncotarget, is specifically overexpressed in 80.6% of cancers. In 2003, we reported that PRL3 promotes cell migration, invasion, and metastasis. Herein, firstly, we show that PRL3 induces Polyploid Giant Cancer Cells (PGCCs) formation. PGCCs constitute stem cell-like pools to facilitate cell survival, chemo-resistance, and tumor relapse. The correlations between PRL3 overexpression and PGCCs attributes raised possibilities that PRL3 could be involved in PGCCs formation. Secondly, we show that PRL3+ PGCCs co-express the embryonic stem cell markers SOX2 and OCT4 and arise mainly due to incomplete cytokinesis despite extensive DNA damage. Thirdly, we reveal that PRL3+ PGCCs tolerate prolonged chemotherapy-induced genotoxic stress via suppression of the pro-apoptotic ATM DNA damage-signaling pathway. Fourthly, we demonstrated PRL3-zumab, a First-in-Class humanized antibody drug against PRL3 oncotarget, could reduce tumor relapse in 'tumor removal' animal model. Finally, we confirmed that PGCCs were enriched in relapse tumors versus primary tumors. PRL3-zumab has been approved for Phase 2 clinical trials in Singapore, US, and China to block all solid tumors. This study further showed PRL3-zumab could potentially serve an 'Adjuvant Immunotherapy' after tumor removal surgery to eliminate PRL3+ PGCC stem-like cells, preventing metastasis and relapse.
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