The Role of TGF-β/SMAD Signaling in Hepatocellular Carcinoma: from Mechanism to Therapy and Prognosis

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with high incidence and mortality, accounting for approximately 90% of liver cancer. The development of HCC is a complex process involving the abnormal activation or inactivation of multiple signaling pathways. Transforming growth factor-β (TGF-β)/Small mothers against decapentaplegic (SMAD) signaling pathway regulates the development of HCC. TGF-β activates intracellular SMADs protein through membrane receptors, resulting in a series of biological cascades. Accumulating studies have demonstrated that TGF-β/SMAD signaling plays multiple regulatory functions in HCC. However, there is still controversy about the role of TGF-β/SMAD in HCC. Because it involves different pathogenic factors, disease stages, and cell microenvironment, as well as upstream and downstream relationships with other signaling pathways. This review will summary the regulatory mechanism of the TGF-β/SMAD signaling pathway in HCC, involving the regulation of different pathogenic factors, different disease stages, different cell populations, microenvironments, and the interaction with microRNAs. In addition, we also introduced small molecule inhibitors, therapeutic vaccines, and traditional Chinese medicine extracts based on targeting the TGF-β/SMAD signaling pathway, which will provide future research direction for HCC therapy targeting the TGF-β/SMAD signaling pathway.

Semaphorin 3C (Sema3C) reshapes stromal microenvironment to promote hepatocellular carcinoma progression

“…Prior research demonstrated that TGF-β promoted HCC growth, invasion, immune evasion, and ECM deposition. 58 Galunisertib, a TGF-β inhibitor, showed promise in slowing advanced HCC development. 59 Combining TGF-β targeting drugs in the future could inhibit HCC proliferation and immune evasion by reducing TGF-β expression, and concurrently down-regulate Sema3C expression to enhance efficacy in reducing drug resistance and preventing tumor recurrence.…”

Hepatitis B virus X protein and TGF-β: partners in the carcinogenic journey of hepatocellular carcinoma

“…The TGF-β pathway plays a crucial role in the progression of HBV-associated HCC. Many drugs targeting the TGF-β pathway have shown promising results in treating HCC ( 164 ). However, the clinical applicability and efficacy of these treatments require further validation through extensive clinical trials.…”