Abstract
Insulin-like Growth Factor (IGF)/IGF-1 Receptor (IGF-1R) signaling is known to regulate stem cell pluripotency and differentiation to trigger cell proliferation, organ development, and tissue regeneration during embryonic development. Unbalanced IGF/IGF-1R signaling can promote cancer cell proliferation and activate cancer reprogramming in tumor tissues, especially in the liver. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, with a high incidence and mortality rate in Asia. Most patients with advanced HCC develop tyrosine kinase inhibitor (TKI)-refractoriness after receiving TKI treatment. Dysregulation of IGF/IGF-1R signaling in HCC may activate expression of cancer stemness that leads to TKI refractoriness and tumor recurrence. In this review, we summarize the evidence for dysregulated IGF/IGF-1R signaling especially in hepatitis B virus (HBV)-associated HCC. The regulation of cancer stemness expression and drug resistance will be highlighted. Current clinical treatments and potential therapies targeting IGF/IGF-1R signaling for the treatment of HCC will be discussed.
Highlights
Treatment leads to increased expression of NANOG and OCT4 in hepatitis B virus (HBV) positive-Hepatocellular carcinoma (HCC) cell lines, but not in HBV negative-HCC cell lines [134]. These findings suggest that HBV induces cancer stemness properties through the activation of Insulin-like Growth Factor (IGF)/IGF-1 Receptor (IGF-1R) signaling (Figure 2)
PI3K/AKT pathways and thereby induce epithelial-mesenchymal transition (EMT) in HCC [141,201]. These results suggest that IGF/IGF-1R signaling may contribute to an increase in mesenchymal characteristics and HCC metastasis
We highlight the evidence for dysregulated IGF/IGF-1R signaling in HCC
Summary
Several risk factors for developing HCC have been identified, including hepatitis virus infection, abnormal fatty acid metabolism, alcoholic liver disease, and toxins [1,3,4]. In five main types of hepatitis virus (type A, B, C, D, and E), types B and C cause the most public health burden, as they are responsible for more than half number of HCC [6]. Targeted therapies (sorafenib and lenvatinib) have been approved for patients with advanced HCC who are not eligible for local treatments. Insulin-like Growth Factor (IGF)/IGF-1R signaling has become a potential target for HCC treatment [14,15]. Elevation in the activation of IGF/IGF-1R signaling in patients with liver cancer caused by hepatitis B infection has been widely reported.
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