Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

Abstract

a b s t r a c t a r t i c l e i n f oHepatocellular carcinoma (HCC) is one of the most lethal malignancies, and is also the fourth most common cancer worldwide with around 700,000 new cases each year. Currently, first line chemotherapeutic drugs used for HCC include fluorouracil, cisplatin, doxorubicin, paclitaxel and mitomycin, but most of these are non-selective cytotoxic molecules with significant side effects. Sorafenib is the only approved targeted therapy by the U.S. Food and Drug Administration for HCC treatment, but patients suffer from various kinds of adverse effects, including hypertension. The signal-transducer-and-activator-of-transcription 3 (STAT3) protein, one of the members of STATs transcription factor family, has been implicated in signal transduction by different cytokines, growth factors and oncogenes. In normal cells, STAT3 activation is tightly controlled to prevent dysregulated gene transcription, whereas constitutively activated STAT3 plays an important role in tumorigenesis through the upregulation of genes involved in anti-apoptosis, proliferation and angiogenesis. Thus, pharmacologically safe and effective agents that can block STAT3 activation have the potential both for the prevention and treatment of HCC. In the present review, we discuss the possible role of STAT3 signaling cascade and its interacting partners in the initiation of HCC and also analyze the role of various STAT3 regulated genes in HCC progression, inflammation, survival, invasion and angiogenesis.

Garcinol, a Polyisoprenylated Benzophenone Modulates Multiple Proinflammatory Signaling Cascades Leading to the Suppression of Growth and Survival of Head and Neck Carcinoma

“…Previous studies have indicated that Src and JAK2 kinase activities cooperate to mediate the constitutive activation of STAT3 (31,40). Our observations suggest that garcinol may block cooperation of Src and JAKs involved in tyrosyl phosphorylation of STAT3.…”

“…STAT3 activation has been reported to be regulated by soluble tyrosine kinases of Src and Janus-activated kinase (JAK) family (31,35). Hence, we determined whether garcinol affected the constitutive activation of these kinases.…”

PKB/Akt-dependent regulation of inflammation in cancer

“…JAK typically responds to a wide range of interleukins (ILs), and subsequently mediates diverse inflammatory responses depending on the individual dimerization patterns of STATs [9,10]. Inflammatory stimuli activate the three signaling nodes along MAPK pathway − extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK) and p38, all of which are involved in malignancy of many types of human cancer [11].…”

AZD1480 Can Inhibit the Biological Behavior of Ovarian Cancer SKOV3 Cells in vitro

“…The signal transducer and activator of transcription (STATs) in signal transduction pathways have multiple family members, in which STAT3 is very important. It was detected to increase abnormally in many solid tumors and participated in malignant tumor cell proliferation, differentiation, invasion, migration and immune escape process (Subramaniam, et al ., 2013;Swiatek-Machado, et al ., 2013). It was proved in vitro and in vivo that the sustained activation of JAK/ STAT3 signal transduction pathway in tissues of head and neck cancer, prostate cancer, breast cancer, colon cancer and other malignant tumors affected the evolution process of biological behavior of tumor cells (Jing et al, 2004;Shin et al, 2009;Lai et al, 2010;Shodeinde et al, 2012).…”