The Bright and the Dark Side of TGF-β Signaling in Hepatocellular Carcinoma: Mechanisms, Dysregulation, and Therapeutic Implications

Abstract

Hepatocellular carcinoma (HCC) is associated with genetic and nongenetic aberrations that impact multiple genes and pathways, including the frequently dysregulated transforming growth factor β (TGF-β) signaling pathway. The regulatory cytokine TGF-β and its signaling effectors govern a broad spectrum of spatiotemporally regulated molecular and cellular responses, yet paradoxically have dual and opposing roles in HCC progression. In the early stages of tumorigenesis, TGF-β signaling enforces profound tumor-suppressive effects, primarily by inducing cell cycle arrest, cellular senescence, autophagy, and apoptosis. However, as the tumor advances in malignant progression, TGF-β functionally switches to a pro-tumorigenic signal, eliciting aggressive tumor traits, such as epithelial–mesenchymal transition, tumor microenvironment remodeling, and immune evasion of cancer cells. On this account, the inhibition of TGF-β signaling is recognized as a promising therapeutic strategy for advanced HCC. In this review, we evaluate the functions and mechanisms of TGF-β signaling and relate its complex and pleiotropic biology to HCC pathophysiology, attempting to provide a detailed perspective on the molecular determinants underlying its functional diversion. We also address the therapeutic implications of the dichotomous nature of TGF-β signaling and highlight the rationale for targeting this pathway for HCC treatment, alone or in combination with other agents.

Redistribution of the SWI/SNF Complex Dictates Coordinated Transcriptional Control over Epithelial–Mesenchymal Transition of Normal Breast Cells through TGF-β Signaling

“…This response appeared to be inhibitory, but not uniformly inverse to the actions of TGF-β in immortalized breast epithelial cells. Rexinoids are unequivocally linked to tumor-suppressing activity, whereas TGF-β has been proposed to behave in a dichotomous manner, depending on the state of malignant transformation of the cell [ 33 ]. While in the context of malignant transformation TGF-β may be a promoter of cell proliferation and invasion, in normal epithelium TGF-β signaling may convey tumor-suppressive effects by inducing cell cycle arrest, apoptosis, and cellular senescence and autophagy [ 34 ].…”

Noncoding RNAs and programmed cell death in hepatocellular carcinoma: Significant role of epigenetic modifications in prognosis, chemoresistance, and tumor recurrence rate

“…Some ncRNAs, such as the miRNA‐449 family, suppress migration of liver cancer cells by transforming the growth factor beta (TGF‐β) signaling pathway through the downregulation of SRY‐related HMG box transcription factor 4 (SOX4), an oncogene frequently detected in HCC and has a pivotal role in EMT, which is linked with tumor onset, metastasis, invasion, and drug resistance (Huang et al, 2021). Activation of TGF‐β signaling is associated with a high rate of HCC tumor recurrence through the downregulation of reelin, a large released extracellular matrix glycoprotein whose decreased expression is related to tumor recurrence in HCC (Gungor et al, 2022). Moreover, this signaling pathway has a pivotal role in cancer metastasis, mostly by promoting EMT.…”

Key oncogenic signaling pathways affecting tumor-infiltrating lymphocytes infiltration in hepatocellular carcinoma: basic principles and recent advances

“…In the early stages of HCC, TGF-β exerts tumor-suppressive effects by inhibiting cellular proliferation and inducing cell cycle arrest. However, in advanced stages, dysregulation of the TGF-β signaling pathway occurs, resulting in the progression of HCC ( 163 ).…”