A Transforming Growth Factor‐β and H19 Signaling Axis in Tumor‐Initiating Hepatocytes That Regulates Hepatic Carcinogenesis

Abstract

Our findings disclose a novel TGF-β and H19 signaling axis via Sox2 in TICs that importantly regulates hepatocarcinogenesis. This article is protected by copyright. All rights reserved.

Targeting Transforming Growth Factor Beta Signaling in Liver Cancer

“…Zhang et al found that TICs deficient in Tgfbr2 form HCC, whereas TICs with intact Tgfbr2 have a reduced capability to form tumors in recipient mice, supporting a tumor‐suppressive role of Tgfbr2 . This study provides direct evidence of tumor‐suppressive effects of TGF‐β signaling within the cancer cells, rather than the tumor stroma or microenvironment.…”

“…Development of HCC is associated with alterations in the transforming growth factor beta (TGF-β) signaling pathway, which plays a critical role in cell proliferation, apoptosis, differentiation, motility, lineage specificity, as well as normal stem cell homeostasis. (1)(2)(3)(4) Mediated by TGF-β ligands that activate TGF-β receptors (TGFBR1 and TGFBR2) to stimulate downstream mothers against decapentaplegic (SMAD) proteins (SMAD2/3/4), the TGF-β signaling pathway positively or negatively regulates transcription of various gene targets involved in diverse biological functions. In addition, many other proteins-including the SMAD3 adaptor spectrin beta, nonerythrocytic 1 (SPTBN1); the TGFBRassociated protein Smad anchor for receptor activation; and the SMAD corepressors SNO/SKI-function as positive or negative regulators of TGF-β signaling.…”

“…This study provides direct evidence of tumor‐suppressive effects of TGF‐β signaling within the cancer cells, rather than the tumor stroma or microenvironment. Other studies in mice with the loss one of allele of TGF‐β pathway members—Tgfbr1, Tgfbr2, Smad3 adaptor Sptbn1, and Smad3—also indicated a tumor‐suppressive role for this pathway . However, those studies could not rule out effects on the tumor stroma or microenvironment for the increase in HCC development in the heterozygous mice.…”

“…The authors defined TICs isolated from the DEN‐injured liver as cells with abundant cluster of differentiation 44, a marker of cancer stem cells, and high abundance of the liver progenitor cell markers epithelial cell adhesion molecule, octamer 4, Sox2 (SRY [sex determining region Y]‐box 2), and Kruppel‐like factor 4. However, they did not experimentally prove that these cells had self‐renewal capacity . Whether these cells are true TICs with some capacity for self‐renewal or DEN‐primed liver progenitors awaits further analysis.…”

“…Thus, there is an urgent need to understand the molecular mechanisms underlying drug resistance and HCC initiation. Development of HCC is associated with alterations in the transforming growth factor beta (TGF‐β) signaling pathway, which plays a critical role in cell proliferation, apoptosis, differentiation, motility, lineage specificity, as well as normal stem cell homeostasis . Mediated by TGF‐β ligands that activate TGF‐β receptors (TGFBR1 and TGFBR2) to stimulate downstream mothers against decapentaplegic (SMAD) proteins (SMAD2/3/4), the TGF‐β signaling pathway positively or negatively regulates transcription of various gene targets involved in diverse biological functions.…”