Abstract
Fibrolamellar hepatocellular carcinomas (FL-HCCs) possess a unique mutation that encodes a chimeric form of protein kinase A (DNAJ-PKAc), which includes a chaperonin binding domain. DNAJ-PKAc retains most of the biochemical properties of the native enzyme, however, and activity remains dependent on cAMP. We thus speculated that a persistent source of cAMP is necessary to promote FL-HCC carcinogenesis, and that neurotensin (NTS) may drive cAMP production in this setting, given that NS serum and tumor levels are elevated in many patients with FL-HCC.We examined expression of NTS pathway components in human FL-HCCs and paired normal livers, and determined the role of NTS in driving proliferation in tumor slice cultures. Cultured hepatocytes were used to determine interactions between NTS and other proliferative pathways, and to determine the effects of NTS on cAMP production and PKA activity.We found that the NTS pathway is up-regulated in human FL-HCCs, and that NTS activates cAMP and PKA in hepatocytes. NTS increases proliferation in the presence of epidermal growth factor (EGF), and NTS-induced proliferation is dependent on NTSR1 and the EGFR/MEK pathway.We conclude that NTS serves as a co-mitogen in FL-HCC, and provides a source of cAMP to facilitate ongoing activation of DNAJ-PKAc.
Highlights
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a primary liver cancer that occurs in young people without underlying liver disease
We show that NTS increases intracellular levels of cAMP as well as PKA activity in hepatocytes, to sustain DNAJ-catalytic subunit of protein kinase A (PKAc) activation in FL-HCCs
In light of these data, we examined the expression of components of this pathway in archived FL-HCCs from our liver tumor biorepository. qRT-PCR analysis of cDNA prepared from four FL-HCCs revealed that expression levels of NTS, NTSR1, NTSR2, and proprotein convertase subtilisin/kexin type 1 (PCSK1) are increased in FL-HCCs as compared to paired normal liver samples (Figure 1A–1D)
Summary
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a primary liver cancer that occurs in young people without underlying liver disease. FL-HCC was mechanistically distinguished from ‘classic’ adult HCC by the discovery of the DNAJB1-PRKACA. This fusion transcript translates a chimeric mutant form where the DNAJ chaperonin binding domain from heat shock protein 40 is fused in frame to the catalytic subunit of protein kinase A (DNAJ-PKAc) [1, 2]. We have previously demonstrated that this mutation results in increased PKAc expression and activation in FL-HCCs, and interestingly, that mutant PKAc activity remains dependent on intracellular cAMP3. G-proteins and GPCRs are key transducers of extracellular signals, and are frequently associated with human cancers [6,7,8]
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