Abstract
Hepatocellular carcinoma (HCC) is a major global health problem and its treatment options have been limited. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor important for various cellular processes. Overexpression and constitutive activation of STAT3 have been frequently found in HCC and associated with poor prognosis. Ample evidence has shown that STAT3 plays pivotal roles in the initiation, progression, metastasis and immune suppression of HCC. Thus, STAT3 has attracted attention as a novel therapeutic target in HCC. Clinical trials have investigated STAT3-targeted therapeutics either as monotherapy or in combination with chemotherapeutic agents, immune checkpoint inhibitors and alternative targeted drugs. Some of these studies have yielded encouraging results. Particularly, napabucasin—a cancer stemness inhibitor targeting STAT3-driven gene transcription—has stood out with its promising clinical efficacy and safety profile. Nonetheless, clinical investigations of STAT3-targeted therapies in HCC are limited and more efforts are strongly urged to evaluate their clinical performance in HCC. Here, we provide a comprehensive review of the roles of STAT3 in HCC and follow by comprehensive analysis of STAT3 targeted strategies.
Highlights
Primary liver cancer is the sixth most prevalent cancer and the second leading cause of cancer mortality worldwide [1]
As appreciated from the abundance of evidence illustrating the oncogenic roles of Signal transducer and activator of transcription 3 (STAT3) in hepatocellular carcinoma (HCC), STAT3 is recognized as a vital oncogene in HCC and may serve as a potential therapeutic target for HCC therapy
Overexpression and constitutive activation of STAT3 in HCC tumors has been found to associate with disease development and patient prognosis
Summary
Primary liver cancer is the sixth most prevalent cancer and the second leading cause of cancer mortality worldwide [1]. For advanced HCC, sorafenib, a multi-tyrosine kinase inhibitor (MTKI), has been the only approved systemic first-line agent for over a decade, until lenvatinib, another MTKI, recently came into play. Their clinical efficacy was suboptimal, with only ~3 months of prolonged survival [10,11]. STAT3 was initially determined to control acute-phase genes in response to interleukin-6 (IL-6) and epidermal growth factor (EGF) during inflammation [18] It belongs to the STAT family of cytoplasmic transcription factors that mediate signal transduction from the plasma membrane to the nucleus in various cellular activities [19]. We summarize the oncogenic roles of STAT3 in HCC and the current clinical development of STAT3-targeted therapeutics
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