Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

Abstract

Transforming growth factor-b (TGF-b) signaling members, TGF-b receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf þ /À mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (Po0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-b signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.

Actin-bundling proteins in cancer progression at a glance

“…TGFb signalling normally acts as a tumour suppressor of colorectal cancer by suppressing growth and promoting apoptosis, but its dysregulation through loss of b2-spectrin inappropriately activates Wnt signalling and promotes tumourigenesis Thenappan et al, 2009) (also see Poster). Embryonic spectrin (also called embryonic liver fodrin, ELF) shows altered expression in some cancers (Table 1) and its loss causes deregulation of cyclin D1 and aberrant cell cycle progression (Kitisin et al, 2007). cadherin receptors that interact extracellularly with the cadherins of neighbouring cells and intracellularly with the actin cytoskeleton (see Poster) (reviewed by Etienne-Manneville, 2011).…”

“…Has also been proposed to be a differentiation marker in colonic neoplasia Reduced expression of spectrin associated with poor prognosis in pancreatic cancer and progression in hepatocellular cancer. Spectrin contributes to platinum chemotherapy resistance (Baek et al, 2011;Jiang et al, 2010;Kitisin et al, 2007;Maeda et al, 2011;Simpson and Page, 1992;Sormunen et al, 1994;Sormunen et al, 1999;Thenappan et al, 2009;Tuominen et al, 1996;Younes et al, 1989) Supervillin Stress fibres and focal adhesions of multiple cell types. Implicated in nuclear architecture…”

Down-regulation of transforming growth factor β receptor type III in hepatocellular carcinoma is not directly associated with genetic alterations or loss of heterozygosity

“…TGFßRII and Smad 4 have been associated with weaker expression levels in HCC tissues when compared to adjacent normal tissues (24). In addition, disruption of TGF-ß signaling through the smad adaptor ELF (embryonic liver protein) has been shown to contribute to the development of HCC in an in vivo model (28). Although these findings suggest that TGF-ß signaling, through TGF-ß receptors, may play a role as a tumor suppressor in HCC progression and development, the involvement of TGFßRIII remains to be elucidated.…”

Transforming growth factor‐β in liver cancer stem cells and regeneration

“…For instance, TBRII is mutated in up to 30% of colon cancers,56 TBRI is mutated in 15% of biliary cancers,57, 58, 59 and SMAD4 is deleted in 40%‐60% of pancreatic cancers and mutated in gastrointestinal cancer 60. Loss of β2SP is observed in human HCC 14, 61, 62, 63. Evidence from Smad4‐knockout mice, which develop head and neck cancers, demonstrates a significant role for Smad4 in promoting genomic stability 64.…”