Downregulation of low‐density lipoprotein receptor class A domain‐containing protein 4 (Ldlrad4) in the liver of rats treated with nongenotoxic hepatocarcinogen to induce transforming growth factor β signaling promoting cell proliferation and suppressing apoptosis in early hepatocarcinogenesis

Abstract

We previously found downregulation of low-density lipoprotein receptor class A domain-containing protein 4 (LDLRAD4), a negative regulator of transforming growth factor (TGF)-β signaling, in glutathione S-transferase placental form (GST-P) expressing (+) pre-neoplastic lesions produced by treatment with nongenotoxic hepatocarcinogens for up to 90 days in rats. Here, we investigated the relationship between LDLRAD4 downregulation and TGFβ signaling in nongenotoxic hepatocarcinogenesis. The transcripts of Tgfb and Hb-egf increased after ≥28 days of treatment. After 84 or 90 days, Snai1 increased transcripts and the subpopulation of GST-P + foci downregulating LDLRAD4 co-expressed TGFβ1, phosphorylated EGFR, or phosphorylated AKT2, and downregulated PTEN, showing higher incidences than those in GST-P + foci expressing LDLRAD4. The subpopulation of GST-P + foci downregulating LDLRAD4 also co-expressed caveolin-1 or TACE/ADAM17, suggesting that disruptive activation of TGFβ signaling through a loss of LDLRAD4 enhances EGFR and PTEN/AKT-dependent pathways via caveolin-1-dependent activation of TACE/ADAM17 during nongenotoxic hepatocarcinogenesis. The numbers of c-MYC + cells and PCNA + cells were higher in LDLRAD4-downregulated GST-P + foci than in LDLRAD4-expressing GST-P + foci, suggesting a preferential proliferation of pre-neoplastic cells by LDLRAD4 downregulation. Nongenotoxic hepatocarcinogens markedly downregulated Nox4 after 28 days and later decreased cleaved caspase 3 + cells in LDLRAD4-downregulated GST-P + foci, suggesting an attenuation of apoptosis by LDLRAD4 downregulation through activation of the EGFR pathway. At the late hepatocarcinogenesis stage in a two-stage model, LDLRAD4 downregulation was higher in adenoma and carcinoma than in pre-neoplastic cell foci, suggesting a role of LDLRAD4 downregulation in tumor development. Our results suggest that

Genome-wide association analysis of the primary feather growth traits of duck: identification of potential Loci for growth regulation

“…MAPK signaling pathway is also important in regulating feather growth and development ( Ji et al, 2021 ). Ito et al (2020) found that downregulation of LDLRAD4 induces transforming growth factor β signaling, promoting cell proliferation and suppressing apoptosis. These results also suggest that DDX10 and LDLRAD4 genes play an important role in feather maturation.…”