Journal of Liver Cancer

Original Article

The dual role of transforming growth factor-beta signatures in human B viral multistep hepatocarcinogenesis: early and late responsive genes: Jeong Eun Yoo, Ji Hae Nahm, Young-Joo Kim, Youngsic Jeon, Young Nyun Park; J Liver Cancer. 2022;22(2):115-124. Published online May 20, 2022; DOI: https://doi.org/10.17998/jlc.2022.04.20

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Background/Aim
Transforming growth factor-beta (TGF-β) has a dichotomous role, functioning as a tumor suppressor and tumor promoter. TGF-β signatures, explored in mouse hepatocytes, have been reported to predict the clinical outcomes of hepatocellular carcinoma (HCC) patients; HCCs exhibiting early TGF-β signatures showed a better prognosis than those with late TGF-β signatures. The expression status of early and late TGF-β signatures remains unclear in defined lesions of human B-viral multistep hepatocarcinogenesis.
Methods
The expression of TGF-β signatures, early and late responsive signatures of TGF-β were investigated and analyzed for their correlation in cirrhosis, low-grade dysplastic nodules (DNs), high-grade DNs, early HCCs and progressed HCCs (pHCCs) by real-time PCR and immunohistochemistry.
Results
The expression levels of TGF-β signaling genes (TGFB1, TGFBR1, TGFBR2 and SMAD4) gradually increased with the progression of hepatocarcinogenesis, peaking in pHCCs. The expression of early responsive genes of TGF-β (GADD45B, FBP1, CYP1A2 and CYP3A4) gradually decreased, and that of the late TGF-β signatures (TWIST and SNAI1) significantly increased according to the progression of multistep hepatocarcinogenesis. Furthermore, mRNA levels of TWIST and SNAI1 were well correlated with those of stemness markers, with upregulation of TGF-β signaling, whereas FBP1 expression was inversely correlated with that of stemness markers.
Conclusions
The enrichment of the late responsive signatures of TGF-β with induction of stemness is considered to be involved in the progression of the late stage of multistep hepatocarcinogenesis, whereas the early responsive signatures of TGF-β are suggested to have tumor-suppressive roles in precancerous lesions of the early stage of multistep hepatocarcinogenesis.

Citations

Citations to this article as recorded by

Structure, unique biological properties, and mechanisms of action of transforming growth factor β
Nataliya Zelisko, Roman Lesyk, Rostyslav Stoika
Bioorganic Chemistry.2024; 150: 107611. CrossRef
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Allan M. Johansen, Steven D. Forsythe, Callum T. McGrath, Grayson Barker, Hugo Jimenez, Ravi K. Paluri, Boris C. Pasche
Clinical Cancer Research.2024; 30(17): 3676. CrossRef
Identification of potential biomarkers for lung adenocarcinoma: a study based on bioinformatics analysis combined with validation experiments
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Frontiers in Oncology.2024;[Epub] CrossRef

Review Articles

Ras Mitogen-activated Protein Kinase Signaling and Kinase Suppressor of Ras as Therapeutic Targets for Hepatocellular Carcinoma: Hyuk Moon, Simon Weonsang Ro; J Liver Cancer. 2021;21(1):1-11. Published online March 31, 2021; DOI: https://doi.org/10.17998/jlc.21.1.1

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5 Citations

Abstract PDF

Hepatocellular carcinoma (HCC) is a high incidence cancer and a major health concern worldwide. Among the many molecular signaling pathways that are dysregulated in HCC, the Ras mitogen-activated protein kinase (Ras/Raf/MAPK) signaling pathway has gained renewed attention from basic and clinical researchers. Mutations in Ras and Raf genes which are known to activate the Ras/Raf/MAPK signaling pathway have been infrequently detected in human HCC; however, the Ras/Raf/MAPK signaling pathway is activated in more than 50% of HCC cases, suggesting an alternative mechanism for the activation of the signaling pathway. Kinase suppressor of Ras acts as a molecular scaffold for facilitating the assembly of Ras/Raf/MAPK signaling pathway components and has been implicated in the regulation of this signaling pathway. In this review, we provide important insights into the cellular and molecular mechanisms involved in the activation of the Ras/Raf/MAPK signaling pathway and discuss potential therapeutic strategies for HCC.

Citations

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Network-Pharmacology-Based Study on Active Phytochemicals and Molecular Mechanism of Cnidium monnieri in Treating Hepatocellular Carcinoma
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Toll-like Receptors and Carcinogenesis: Geum-Youn Gwak; Journal of the Korean Liver Cancer Study Group. 2011;11(2):97-103. Published online September 30, 2011

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Abstract PDF: Toll-like receptors are a family of pattern recognition receptors that allow the immune system to sense molecules that are present in most classes of pathogens such as bacteria and viruses, but not the host, and to coordinate defense mechanisms against these pathogens. Emerging evidence also suggests that TLRs have an important role in maintaining tissue homeostasis by regulating the inflammatory and tissue repair responses to injury. Due to the important role in inflammation, tissue regeneration and fibrogenesis, TLRs are potential candidates to mediate effects of the innate immune system on carcinogenesis. Although the role of TLRs in carcinogenesis is far from being completely understood, current data suggest a dual role of TLRs in carcinogenesis: anti-tumor effects versus tumor-promoting effects. Here we discuss how TLRs function in the context of carcinogenesis.

The Role of TIS21/BTG2/PC3 during Hepatocarcinogenesis: Tae Jun Park; Journal of the Korean Liver Cancer Study Group. 2011;11(2):130-135. Published online September 30, 2011

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Abstract PDF: A functional and biochemical features of TIS21(/BTG2/PC3) was explored in hepatocarcinogenesis. Growth of hepatocellular carcinoma (HCC), developed by a single injection of diethylnitrosamine (DEN) was significantly higher in the TIS21 knockout mice at 9 months. Expression of BTG2/TIS21 was significantly lower in both human and mouse hepatocellular carcinoma than in the surrounding normal tissues. Over-expression of TIS21 inhibited cell proliferation and tumorigenic potential of Huh7 hepatoma cells. At the molecular mechanistic level, TIS21 inhibited FoxM1 phosphorylation, by reducing cyclin B1-cdk1 activity. Furthermore, TIS21 inhibited FoxM1 transcriptional activity. In conclusion, TIS21 negatively regulated hepatocarcinogenesis in part by disruption of the FoxM1-cyclin B1 regulatory loop, thereby inhibiting proliferation of transformed cells developed in mouse and human livers.

Prediction of Tumor Biology in Hepatocellular Carcinoma: Won Kim; Journal of the Korean Liver Cancer Study Group. 2009;9(1):1-6. Published online June 30, 2009

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Abstract PDF: Hepatocellular carcinoma (HCC) surveillance programs have led to an increase in the adoption of radical therapies. Nevertheless, HCCs often present at an advanced stage and the prognosis remains dismal even after resection due to the high rate of recurrence. The study of tumor biology is important to predict clinical outcome enabling more appropriate therapeutic decisions for HCC patients. Understanding molecular mechanisms of hepatocarcinogenesis may also lead to effective strategies in chemoprevention. However, current staging systems based on clinicopathologic factors are limited in prognostic prediction. Recently, there has been great interest in the study of gene expression profile in relation to prognosis of HCC. Global gene expression profiling may be the most appropriate technology to unravel the pathogenesis of HCC and explore its heterogeneous origin. The elucidation of tumor biology of HCC is of paramount clinical importance in the new era of molecular target therapy.

Case Report

Small Hepatocellular Carcinoma in Dysplastic Nodule: Chang Wook Kim, Eun Sun Jung, Jong Young Choi, Jeong Won Jang, Si Hyun Bae, Seung Kew Yoon, Chang Don Lee, Kyu Won Chung, Hee Sik Sun; Journal of the Korean Liver Cancer Study Group. 2004;4(1):50-54. Published online June 30, 2004

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Abstract PDF: Dysplastic nodule (DN) is considered as precancerous lesion of hepatocellular carcinoma (HCC). There are several evidences to support the theory about multistep progression of hepatocarcinogenesis. Recently we experienced a patient with HCC of the odule-in-nodule pattern, namely small HCC within DN, which supported the multistep theory of hepatocarcinogenesis. The tumor was seen as a 3 cm, arterial enhancing mass with delayed wash-out patterns in the segment Ⅶ at helical CT. The patient was treated by surgical resection. A 3.0×2.5 cm mass was seen in the resected specimen. A 2.2×1.5 cm, smaller nodule was observed within this mass, i.e. the odule-in-nodule pattern. Microscopically, various grades of HCC foci were seen within high grade DN. Because DN does not always progress to HCC, further studies are needed to evaluate what kind of DN has the high possibility of progressing of HCC at last.

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