The Therapeutic Relevance of Co-Targeting Wnt-Hh Signalling Pathways in Hepatocellular Carcinoma
Year: 2020
Type: article
Abstract: Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed primary liver cancer and is also a major cause of cancer-related mortality across the world [1].Additionally, it is one of the cancers which is admittedly refractory to chemotherapy [2] to radiotherapy and to combination treatment [3].The aetiology of HCC is diverse including viral factors like infection with hepatitis B or hepatitis C virus infection (HBV and HCV); non-viral factors like alcohol consumption, obesity and other metabolic syndrome; aflatoxin exposure; hereditary factor, and genetic predisposition like mutations in important signalling pathway genes [1,4].Hepatocarcinogenesis is a multistep process, progressing from a normal hepatocyte to transformed phenotype as a result of the accumulation of aberrant genetic and epigenetic modifications and activation of various signalling pathways [5].Two major signalling pathways found to be deregulated in HCC are Wnt and Hedgehog (Hh) pathways [6].These two pathways play key roles in embryogenesis, morphogenesis, tissue patterning, angiogenesis, stem cell maintenance, tumorigenesis, and drug AbstractHepatocellular carcinoma (HCC) is one of the most commonly diagnosed primary liver cancer and is refractory to most of the chemotherapeutic drugs available.Multiple signalling pathways are deregulated in HCC, and two important developmental signalling pathways which are deregulated in HCC are Wnt and Hh signalling pathways.In various cancer models both pathways have been found to interact with each other at different levels and this interaction is known to play important role in the pathophysiology of those cancers like pancreatic cancer, colon cancer, and basal cell carcinoma.Previously we have shown that the Wnt and Hh pathways correlate positively and play an important role in the progression of hepatocarcinogenesis in rodent model.Our previously published data suggested that the investigation of cross-talk between these two pathways holds potential for identification of better HCC treatment strategies.In the present study we utilized pharmacological inhibitors of Wnt and Hh signalling pathways to unravel the functional interaction between these two pathways.We studied the impact of inhibition or up-regulation of Wnt signalling pathway on Hh signalling pathway outcome.We also investigated the chemo-preventive action of Sulindac Sulphide, a Wnt/β-catenin pathway inhibitor on tumorigenesis in animal model of hepatocarcinogenesis. Our study elaborated the nature of cross-talk between these two well known aberrant signalling pathways in HCC which would further pave the way for development of better combination therapy approach for targeting these two pathways in HCC.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W3009999628