Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which will affect more than a million people by the year 2025. However, current treatment options have limited benefits. Nonalcoholic fatty liver disease (NAFLD) is the fastest growing factor that causes HCC in western countries, including the United States. In addition, NAFLD co-morbidities including obesity, type 2 diabetes mellitus (T2DM), and cardiovascular diseases (CVDs) promote HCC development. Alteration of metabolites and inflammation in the tumor microenvironment plays a pivotal role in HCC progression. However, the underlying molecular mechanisms are still not totally clear. Herein, in this review, we explored the latest molecules that are involved in obesity, T2DM, and CVDs-mediated progression of HCC, as they share some common pathologic features. Meanwhile, several therapeutic options by targeting these key factors and molecules were discussed for HCC treatment. Overall, obesity, T2DM, and CVDs as chronic metabolic disease factors are tightly implicated in the development of HCC and its progression. Molecules and factors involved in these NAFLD comorbidities are potential therapeutic targets for HCC treatment.
Highlights
Hepatocellular carcinoma is the most common type of primary liver cancer, with a global case number larger than one million by 2025 [1]
This study showed that the HOMA-IR score was significantly higher in nonalcoholic steatohepatitis (NASH) patients than that in NALFD patients, which may cause a higher co-incidence of NASH with type 2 diabetes mellitus (T2DM)
nonalcoholic fatty liver disease (NAFLD) comorbidities obesity, T2DM, and cardiovascular diseases (CVDs) are risk factors that contribute to Hepatocellular carcinoma (HCC) initiation and progression
Summary
Hepatocellular carcinoma is the most common type of primary liver cancer, with a global case number larger than one million by 2025 [1]. Factors including hepatitis viral infection, nonalcoholic fatty liver disease (NAFLD), alcohol abuse, and dietary toxins (e.g., aflatoxins) can cause the initiation and development of HCC [2]. Both genetic and epigenetic factors can promote HCC progression [3], such as mutation of programmed cell death-1 (PDCD1, rs10204525 C > T mutation) and DNA methylation. Gut microbiota and their-associated factors such as metabolites and components play important roles in the pathogenesis of obesity, T2DM, CVDs, NAFLD, and HCC [6,7,8,9]. In addition to gut microbiota, several other factors such as chronic inflammation, insulin resistance, alteration of metabolites have been reported to be associated with obesity, T2DM, CVDs, as well as NAFLD, which can induce HCC initiation and progression. The causing factors and treatment options of NAFLD-related HCC have been reported in another paper recently [3]
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