Pivotal roles of glycogen synthase-3 in hepatocellular carcinoma

Cervello, Melchiorre; Augello, Giuseppa; Cusimano, Antonella; Emma, Maria Rita; Balasus, Daniele; Azzolina, Antonina; McCubrey, James A.; Montalto, Giuseppe

doi:10.1016/j.jbior.2017.06.002

Cited by 43 publications

(30 citation statements)

References 171 publications

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“…Moreover, it has also been shown that glycogen synthase-3 (GSK3) induces invasion and EMT through negative regulation of TGF-b signaling (Cervello et al, 2017). We previously showed that the disruption of Tgfbr2 or Smad4 in Apc D716 mice resulted in the induction of submucosal invasion of intestinal tumors, confirming the tumor-suppressor role of the TGFβ pathway (Kitamura et al, 2007;Oshima et al, 2015).…”

Section: Inflammatory Pathway For Malignant Progression (Tgf-b Signalmentioning

confidence: 83%

The inflammatory microenvironment that promotes gastrointestinal cancer development and invasion

Echizen

Oshima

Nakayama

et al. 2018

Advances in Biological Regulation

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Accumulating evidence has indicated that the inflammatory response is important for tumor promotion. However, the mechanisms underlying the induction of the inflammatory response in cancer tissues and how it promotes tumorigenesis remain poorly understood. We constructed several mouse models that develop inflammation-associated gastric and intestinal tumors and examined the in vivo mechanisms of tumorigenesis. Of note, the activation of cyclooxygenase-2 (COX-2)/prostaglandin E (PGE) pathway and Toll-like receptor (TLR)/MyD88 signaling cooperatively induced the generation of an inflammatory microenvironment, which is required for early-stage tumorigenesis. The inflammatory response in the stroma induces TNF-α signaling in tumor cells, and the NOX1/ROS signaling pathway is activated downstream. In addition, the inflammatory pathway induces the expression of TLR2 in tumor epithelial cells. Both the NOX1/ROS and TLR2 pathways in tumor cells contribute to the acquisition and maintenance of stemness, which is an important tumor-promoting mechanism stimulated by inflammation. We also found that inflammation promotes malignant processes, like submucosal invasion, of TGF-β signaling-suppressed tumor cells through the activation of MMP2 protease. Moreover, we showed that mutant p53 induces innate immune and inflammatory signaling in the tumor stroma by a gain-of-function mechanism of mutant p53, which may explain the "cancer-induced inflammation" mechanism. These results indicate that the regulation of the inflammatory microenvironment via the inhibition of the COX-2/PGE and TLR/MyD88 pathways in combination will be an effective preventive or therapeutic strategy against gastrointestinal cancer development and malignant progression, especially those carrying p53 gain-of-function mutations.

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Section: Inflammatory Pathway For Malignant Progression (Tgf-b Signalmentioning

confidence: 83%

The inflammatory microenvironment that promotes gastrointestinal cancer development and invasion

Echizen

Oshima

Nakayama

et al. 2018

Advances in Biological Regulation

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“…An issue regarding ATP-competitive inhibitors may concern their lack of specificity; namely, they interfere with the phosphorylation of many substrates, giving potential oncogenic effects [ 3 ]. Some GSK-3 inhibitors have been used in clinical trials and are well-tolerated in cancer patients [ 117 ]. Significant clinical improvements have been shown in cutaneous T-cell lymphoma patients treated with valproate, which inhibits either GSK-3 isoforms [ 118 ].…”

Section: Gsk-3 β -Specific Inhibitors: Using Gsmentioning

confidence: 99%

Multifaceted Roles of GSK-3 in Cancer and Autophagy-Related Diseases

Mancinelli

Carpino

Petrungaro

et al. 2017

Oxidative Medicine and Cellular Longevity

174

128

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GSK-3 is a ubiquitously expressed serine/threonine kinase existing as GSK-3α and GSK-3β isoforms, both active under basal conditions and inactivated upon phosphorylation by different upstream kinases. Initially discovered as a regulator of glycogen synthesis, GSK-3 is also involved in several signaling pathways controlling many different key functions. Here, we discuss recent advances regarding (i) GSK-3 structure, function, regulation, and involvement in several cancers, including hepatocarcinoma, cholangiocarcinoma, breast cancer, prostate cancer, leukemia, and melanoma (active GSK-3 has been shown to induce apoptosis in some cases or inhibit apoptosis in other cases and to induce cancer progression or inhibit tumor cell proliferation, suggesting that different GSK-3 modulators may address different specific targets); (ii) GSK-3 involvement in autophagy modulation, reviewing signaling pathways involved in neurodegenerative and liver diseases; (iii) GSK-3 role in oxidative stress and autophagic cell death, focusing on liver injury; (iv) GSK-3 as a possible therapeutic target of natural substances and synthetic inhibitors in many diseases; and (v) GSK-3 role as modulator of mammalian aging, related to metabolic alterations characterizing senescent cells and age-related diseases. Studies summarized here underline the GSK-3 multifaceted role and indicate such kinase as a molecular target in different pathologies, including diseases associated with autophagy dysregulation.

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“…Liver cancer is the third most fatal cancer in the world, with mortality rates of ≤0.49‰ and poor prognosis within the last 5 years (1)(2)(3). Although the underlying mechanisms of liver cancer development remains to be investigated, accumulating evidence has implicated that tumor cell proliferation contributes to the process of oncogenesis (4).…”

Section: Introductionmentioning

confidence: 99%

17β‑hydroxysteroid dehydrogenase�4 induces liver cancer proliferation‑associated genes via STAT3 activation

et al. 2019

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Accumulating evidence has implicated that the activation of signal transducer and activator of transcription 3 (STAT3) contributes to the progression of liver cancer by affecting the expression of proliferation-associated genes. A previous study reported that elevated levels of 17β-hydroxysteroid dehydrogenase 4 (HSD17B4) are observed in patients with liver cancer. The current study investigated how upregulated HSD17B4 expression promoted the expression of proliferation-associated genes in rats with liver cancer. HSD17B4 expression in rats with liver cancer was significantly increased compared with the control group as determined by reverse transcription-quantitative polymerase chain reaction and western blot assays. Immunohistochemical results revealed that STAT3 activation was positively correlated with increased HSD17B4 expression in tumor tissues from patients with liver cancer. Western blot results further suggested that HSD17B4 overexpression increased STAT3 activation via the protein kinase B and the mitogen-activated protein kinase/extracellular-signal-regulated kinase signaling pathways in HepG2 cells. The present study suggested that overexpression may promote HepG2 proliferation by enhancing expression of various downstream targets of STAT3. Targeted inhibition of HSD17B4 may describe a novel approach in the prevention and treatment of liver cancer.

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Pivotal roles of glycogen synthase-3 in hepatocellular carcinoma

Cited by 43 publications

References 171 publications

The inflammatory microenvironment that promotes gastrointestinal cancer development and invasion

The inflammatory microenvironment that promotes gastrointestinal cancer development and invasion

Multifaceted Roles of GSK-3 in Cancer and Autophagy-Related Diseases

17β‑hydroxysteroid dehydrogenase�4 induces liver cancer proliferation‑associated genes via STAT3 activation

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