Abstract
Paternally expressed gene 10 (PEG10) has been associated with neuroendocrine muscle-invasive bladder cancer (MIBC), a subtype of the disease with the poorest survival. In this work, we further characterized the expression pattern of PEG10 in The Cancer Genome Atlas database of 412 patients with MIBC, and found that, compared with other subtypes, PEG10 mRNA level was enhanced in neuroendocrine-like MIBC and highly correlated with other neuroendocrine markers. PEG10 protein level also associated with neuroendocrine markers in a tissue microarray of 82 cases. In bladder cancer cell lines, PEG10 expression was induced in drug-resistant compared with parental cells, and knocking down of PEG10 resensitized cells to chemotherapy. Loss of PEG10 increased protein levels of cell-cycle regulators p21 and p27 and delayed G1-S-phase transition, while overexpression of PEG10 enhanced cancer cell proliferation. PEG10 silencing also lowered levels of SLUG and SNAIL, leading to reduced invasion and migration. In an orthotopic bladder cancer model, systemic treatment with PEG10 antisense oligonucleotide delayed progression of T24 xenografts. In summary, elevated expression of PEG10 in MIBC may contribute to the disease progression by promoting survival, proliferation, and metastasis. Targeting PEG10 is a novel potential therapeutic approach for a subset of bladder cancers.
Highlights
Muscle-invasive bladder cancer (MIBC) is highly aggressive with poor survival rates [1, 2]
The expression pattern of Paternally expressed gene 10 (PEG10) was investigated in MIBC cases from The Cancer Genome Atlas (TCGA) database, which consists of 408 samples with RNA-seq data from chemotherapy-na€ve, muscle-invasive, high-grade urothelial tumors [3]
PEG10 mRNA was highly expressed in the neuronal subtype MIBC compared with the basal, luminal, luminal-infiltrated, and luminal-papillary subtypes (Fig. 1A)
Summary
Muscle-invasive bladder cancer (MIBC) is highly aggressive with poor survival rates [1, 2]. Thorough understanding of disease progression is needed to guide treatments for this common, highly lethal malignancy. Recent molecular characterization from The Cancer Genome Atlas (TCGA) identified driver genes and pathways of MIBC [3]. Forty percent to 50% of MIBCs have inactivating mutations or reduced expression of RB1, which is strongly associated with poor clinical outcomes [5, 6]. Loss-of-function mutations of TP53 are present in up to 60% of MIBCs [7] and are associated with disease poor outcomes [8, 9]. Abnormalities of RB1 and TP53 genes coexist among 40%–50% of MIBCs [10]
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