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

SIMPLE SUMMARY: Transforming growth factor β (TGF-β) signaling is a preeminent regulator of diverse cellular and physiological processes. Frequent dysregulation of TGF-β signaling has been implicated in cancer. In hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer, the autocrine and paracrine effects of TGF-β have paradoxical implications. While acting as a potent tumor suppressor pathway in the early stages of malignancy, TGF-β diverts to a promoter of tumor progression in the late stages, reflecting its bright and dark natures, respectively. Within this context, targeting TGF-β represents a promising therapeutic option for HCC treatment. We discuss here the molecular properties of TGF-β signaling in HCC, attempting to provide an overview of its effects on tumor cells and the stroma. We also seek to evaluate the dysregulation mechanisms that mediate the functional switch of TGF-β from a tumor suppressor to a pro-tumorigenic signal. Finally, we reconcile its biphasic nature with the 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.