Transcriptionally Active Androgen Receptor Splice Variants Promote Hepatocellular Carcinoma Progression

Abstract

Owing to the marked sexual dimorphism of hepatocellular carcinoma (HCC), sex hormone receptor signaling has been implicated in numerous aspects of liver cancer pathogenesis. We sought to reconcile the clear contribution of androgen receptor (AR) activity that has been established in preclinical models of HCC with the clinical failure of AR antagonists in patients with advanced HCC by evaluating potential resistance mechanisms to AR-targeted therapy. The AR locus was interrogated for resistance-causing genomic modifications using publicly available primary HCC datasets (1,019 samples). Analysis of HCC tumor and cell line RNA-seq data revealed enriched expression of constitutively active, treatment-refractory AR splice variants (AR-SV). HCC cell lines expressed C-terminal-truncated AR-SV; 28 primary HCC samples abundantly expressed AR-SV. Low molecular weight AR species were nuclear localized and constitutively active. Furthermore, AR/ AR-SV signaling promoted AR-mediated HCC cell progression and conferred resistance to AR antagonists. Ligand-dependent and -independent AR signaling mediated HCC epithelial-tomesenchymal transition by regulating the transcription factor SLUG. These data suggest that AR-SV expression in HCC drives HCC progression and resistance to traditional AR antagonists. Novel therapeutic approaches that successfully target AR-SVs may be therapeutically beneficial for HCC.Significance: Treatment-refractory, constitutively active androgen receptor splice variants promote hepatocellular carcinoma progression by regulating the epithelial-to-mesenchymal transition pathway.

Splicing factor PRPF6 upregulates oncogenic androgen receptor signaling pathway in hepatocellular carcinoma

“…As a transcription factor, AR mainly contains ligand‐independent AF1 and AF2, required for cognate ligand binding. In addition, it has been reported that AR‐V7 is a well described variant in prostate cancer and HCC 11,13 . We thus turned to examine the effect of PRPF6 on the transactivation mediated by AR‐AF1, AR‐AF2, or AR‐V7.…”

“…Androgen receptor, as a member of the nuclear receptor superfamily, is a transcription factor activated by ligand (androgen, DHT) to induce a series of target genes. Growing evidence reveals that AR‐induced target genes transcription is important for the development of HCC progression, although the effect of antiandrogen therapy is not satisfactory in clinical liver cancer 8‐11 . This indicates that the AR signaling pathway and the regulation of the oncogenic AR action would be more complicated in HCC.…”

Proteomic analysis revealed common, unique and systemic signatures in gender-dependent hepatocarcinogenesis

“…Consistently, our report showed that orchiectomy significantly reduced serum testosterone level and hepatic tumorigenesis of Ras-Tg males [63] and artificially increased serum testosterone levels of Ras-Tg females significantly promoted the hepatotumorigenesis (data not show). Although the overexpression or variant of AR has been considered to play a dominant role in HCC [64][65][66], others showed decreased expression of AR in HCC [57,67,68]. These conflicting results regarding the expression and role of AR in HCCs required more detailed investigations [58].…”

Uncovering the Mechanism of the Effects of Pien-Tze-Huang on Liver Cancer Using Network Pharmacology and Molecular Docking

“…The expression of AR-SV in liver cancer leads to the progress of liver cancer and the resistance to traditional AR antagonists. The successful therapy targeting AR-SVs is beneficial to liver cancer [ 46 ]. Target prediction and pathway enrichment revealed that 14 bioactive compounds (notoginsenoside R1, ginsenoside Re, ginsenoside Rg1, ginsenoside Rb1, ginsenoside Rd, chenodeoxycholic acid, cholic acid, glycodeoxycholic acid hydrate, deoxycholic acid, taurocholic acid, astragaloside A, ginsenoside Rd, sodium taurodeoxylate, and taurochenodeoxycholic acid) act on pathways in cancer signaling pathway and play a therapeutic role in liver cancer by regulating the expression of AR.…”