Abstract
Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is a ubiquitous RNA splicing factor that is overexpressed and prognostically relevant in various human cancer types. To study the impact of hnRNPA1 expression in prostate cancer, we analyzed a tissue microarray containing 17,747 clinical prostate cancer specimens by immunohistochemistry. hnRNPA1 was expressed in normal prostate glandular cells but often overexpressed in cancer cells. hnRNPA1 immunostaining was interpretable in 14,258 cancers and considered strong in 33.4%, moderate in 45.9%, weak in 15.3%, and negative in 5.4%. Moderate to strong hnRNPA1 immunostaining was strongly linked to adverse tumor features including high classical and quantitative Gleason score, lymph node metastasis, advanced tumor stage, positive surgical margin, and early biochemical recurrence (p < 0.0001 each). The prognostic impact of hnRNPA1 immunostaining was independent of established preoperatively or postoperatively available prognostic parameters (p < 0.0001). Subset analyses revealed that all these associations were strongly driven by the fraction of cancers lacking the TMPRSS2:ERG gene fusion. Comparison with other key molecular data that were earlier obtained on the same TMA showed that hnRNPA1 overexpression was linked to high levels of androgen receptor (AR) expression (p < 0.0001) as well as presence of 9 of 11 chromosomal deletions (p < 0.05 each). A strong association between hnRNPA1 upregulation and tumor cell proliferation that was independent from the Gleason score supports a role for tumor cell aggressiveness. In conclusion, hnRNPA1 overexpression is an independent predictor of poor prognosis in ERG-negative prostate cancer. hnRNPA1 measurement, either alone or in combination, might provide prognostic information in ERG-negative prostate cancer.
Highlights
Prostate cancer is the most prevalent cancer in men in Western societies [46]
Heterogeneous nuclear ribonucleoprotein A1 is the most abundantly expressed member of a family of more than 20 related proteins. hnRNPs form “beads on a string” like highly dynamic complexes that bind nascent nuclear RNAs and regulate their transcription, splicing, stability, export from the nucleus, and translation [41]. hnRNPA1-dependent alternative splicing affects many genes related to growth signaling and DNA repair, including for example SRC kinase, the HRAS oncogene, and the BRCA1 tumor suppressor [17]
Overexpression of hnRNPA1 has been reported from gliomas, lymphomas, myelomas, leukemias, and breast, colorectal, gastric, and lung cancers [2, 4, 7, 16, 38, 44, 47], and was linked to poor prognosis in hepatocellular carcinoma [50] and breast cancer [37]
Summary
Despite a rather indolent clinical course of most prostate cancers, this disease still represents the third most common cause of cancer-related death in men. There is hope that a deeper insight in disease biology will eventually identify clinically applicable molecular markers that implicate a more reliable prediction of prostate cancer aggressiveness. HnRNPA1 has been reported to bind to telomeric sequences where it stimulates telomerase activity and contributes to telomere length regulation and maintenance [41]. It is, not surprising that deregulation—typically overexpression—of hnRNPA1 has been linked to a variety of diseases including cancer. Data on the prevalence and clinical significance of hnRNPA1 protein expression in prostate cancer are still lacking in the literature
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