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Review
. 2020 Mar 18;7(1):HEP18.
doi: 10.2217/hep-2020-0001.

JAK/STAT signaling in hepatocellular carcinoma

Justin Jit Hin Tang  1 , Dexter Kai Hao Thng  2 , Jhin Jieh Lim  2 , Tan Boon Toh  1
Affiliations
Review

JAK/STAT signaling in hepatocellular carcinoma

Justin Jit Hin Tang et al. Hepat Oncol. .

Abstract

Liver cancer is the second most lethal cancer in the world with limited treatment options. Hepatocellular carcinoma (HCC), which accounts for more than 80% of all liver cancers, has had increasing global incidence over the past few years. There is an urgent need for novel and better therapeutic intervention for HCC patients. The JAK/STAT signaling pathway plays a multitude of important biological functions in both normal and malignant cells. In a subset of HCC, JAK/STAT signaling is aberrantly activated, leading to dysregulation of downstream target genes that controls survival, angiogenesis, stemness, immune surveillance, invasion and metastasis. In this review, we will focus on the role of JAK/STAT signaling in HCC and discuss the current clinical status of several JAK/STAT inhibitors.

Keywords: JAK/STAT signaling; hepatocarcinogenesis; hepatocellular carcinoma; liver cancer; targeted therapy.

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Conflict of interest statement

Financial & competing interests disclosure TB Toh gratefully acknowledges financial support from N.1 Translational Core. The other authors state no conflict of interest. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.
Figure 1.. JAK/STAT signaling pathway overview.
(1) Ligands such as cytokines and growth factors bind to transmembrane receptors, activating receptor-associated JAKs. (2) JAKs phosphorylate cytoplasmic tails of receptors, (3) recruiting STATs to the receptor and become phosphorylated by JAKs. (4) Activated STATs dimerize and (5) translocate into the nucleus where they bind to DNA and (6) activate transcription of target genes such as those involved in regulating cell growth.
Figure 2.
Figure 2.. Schematic structures of JAK and STAT proteins.
(A) JAK proteins contain a FERM domain that associates with receptors, a SH2 domain that binds phosphorylated tyrosine residues and two kinase domains JH1 and JH2. Arrowheads indicate phosphorylation sites (tyrosine residues) required for JAK activation. (B) STAT proteins contain a coiled coil domain for dimerization, a DBD, a SH2 domain and a TAD for transcriptional activation of target genes. Arrowheads indicate the conserved tyrosine residue that needs to be phosphorylated for STAT activation. N and C represents the amino- and carboxy-terminal ends respectively. DBD: DNA-binding domain; TAD: Transactivation domain.
Figure 3.
Figure 3.. The role of STAT3 in hepatocellular carcinoma.
The regulation of target genes and proteins by STAT3 promotes the progression of hepatocellular carcinoma by contributing to key hallmarks of tumorigenesis. Shown in green are genes and proteins which are upregulated while genes in red are inhibited by STAT3 activation.
See this image and copyright information in PMC

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