Abstract
HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC.
Highlights
Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, ranked sixth in incidence and fourth in mortality, with 841,080 new cases and 781,631 deaths worldwide (Ko et al, 2020)
We investigated the involvement of the NF-κB and mitogen-activated protein kinase (MAPK) signaling in hypoxia-inducible facto-1α (HIF-1α) regulation
There was a marked increase in liver weight and the liver index in the NDEA group compared to the control group, while the STGPT 20, 40, and 80 groups showed a significant reduction in their liver weights and indices compared to that of the NDEA group (Table 2)
Summary
Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, ranked sixth in incidence and fourth in mortality, with 841,080 new cases and 781,631 deaths worldwide (Ko et al, 2020). Over the past three decades, the global incidence of liver cancer has risen by 75%. Hepatitis B and C virus infection and cirrhosis are among the risk factors for HCC (Singal et al, 2020). HCC typically arises in a background of chronic liver disease and is often discovered at later stages, making treatment choices more complex. The HCC needs to be treated, but the underlying liver disease will often require medical attention. The management of HCC requires a multidisciplinary approach, including the gastroenterologist, oncologist, interventional radiologist, and surgeon
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