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Review
. 2022 Jul 28;28(28):3535-3554.
doi: 10.3748/wjg.v28.i28.3535.

Peroxisome proliferator-activated receptor gamma as a therapeutic target for hepatocellular carcinoma: Experimental and clinical scenarios

Swati Katoch  1   2 , Vinesh Sharma  1   2 , Vikram Patial  1   3
Affiliations
Review

Peroxisome proliferator-activated receptor gamma as a therapeutic target for hepatocellular carcinoma: Experimental and clinical scenarios

Swati Katoch et al. World J Gastroenterol. .

Abstract

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Viral hepatitis is a significant risk factor for HCC, although metabolic syndrome and diabetes are more frequently associated with the HCC. With increasing prevalence, there is expected to be > 1 million cases annually by 2025. Therefore, there is an urgent need to establish potential therapeutic targets to cure this disease. Peroxisome-proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor that plays a crucial role in the patho-physiology of HCC. Many synthetic agonists of PPARγ suppress HCC in experimental studies and clinical trials. These synthetic agonists have shown promising results by inducing cell cycle arrest and apoptosis in HCC cells and preventing the invasion and metastasis of HCC. However, some synthetic agonists also pose severe side effects in addition to their therapeutic efficacy. Thus natural PPARγ agonists can be an alternative to exploit this potential target for HCC treatment. In this review, the regulatory role of PPARγ in the pathogenesis of HCC is elucidated. Furthermore, the experimental and clinical scenario of both synthetic and natural PPARγ agonists against HCC is discussed. Most of the available literature advocates PPARγ as a potential therapeutic target for the treatment of HCC.

Keywords: Anticancer; Hepatocellular carcinoma; Natural agonists; Peroxisome proliferator-activated receptor-γ; Thiazolidinediones.

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Conflict of interest statement

Conflict-of-interest statement: The authors have no conflict of interests to declare.

Figures

Figure 1
Figure 1
General structure and ligand-activated transcription of peroxisome proliferator-activated receptor-gamma. A: Peroxisome proliferator-activated receptor (PPAR) structure includes four distinct structural domains A/B, C, D, and E/F; B: Ligand-activated transcription of PPARγ, which includes heterodimerization with nuclear receptor retinoid X receptor (RXR) and binding with peroxisome proliferator response elements located in the target genes through the DNA-binding domain (DBD). In the absence of ligand, PPAR is linked with the corepressor complex, whereas, in the presence of ligand, it is associated with the coactivator complex. LBD: Ligand-binding domain; PPRE: Peroxisome proliferator response element.
Figure 2
Figure 2
Schematic diagram showing the protective effect of peroxisome proliferator-activated receptor γ against the progression of hepatocellular carcinoma. Activated peroxisome proliferator-activated receptor γ (PPARγ) interacts with multiple pathways, leading to cell cycle arrest, apoptosis, inhibition of cell proliferation, and cell metastasis in hepatocellular carcinoma. BAX: B-cell lymphoma 2 (Bcl-2)-associated X protein; IκBα: Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibition alpha; IL: Interleukin; TIMP: Tissue inhibitor of metalloproteinases; MMP: Matrix metalloproteinase; ECM: Extracellular matrix; αSMA: Alpha-smooth muscle actin; TGFβ: Transforming growth factor beta; iNOS: Inducible nitric oxide synthase; TNFα: Tumor necrosis factor alpha; APF1: Apoptotic protease activating factor 1.
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