Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world. Previous studies have identified the importance of alcohol and hepatitis B (HBV) infection on HCC carcinogenesis, indicating synergy in the methods by which these etiologies advance cancer. However, the specific molecular mechanism behind alcohol and HBV-mediated carcinogenesis remains unknown. Because the microbiome is emerging as a potentially important regulator of cancer development, this study aims to classify the effects of HBV and alcohol on the intratumoral liver microbiome. RNA-sequencing data from The Cancer Genome Atlas (TCGA) were used to infer microbial abundance. This abundance was then correlated to clinical variables and to cancer and immune-associated gene expression, in order to determine how microbial abundance may contribute to differing cancer progression between etiologies. We discovered that the liver microbiome is likely oncogenic after exposure to alcohol or HBV, although these etiological factors could decrease the abundance of a few oncogenic microbes, which would lead to a tumor suppressive effect. In HBV-induced tumors, this tumor suppressive effect was inferred based on the downregulation of microbes that induce cancer and stem cell pathways. Alcohol-induced tumors were observed to have distinct microbial profiles from HBV-induced tumors, and different microbes are clinically relevant in each cohort, suggesting that the effects of the liver microbiome may be different in response to different etiological factors. Collectively, our data suggest that HBV and alcohol operate within a normally oncogenic microbiome to promote tumor development, but are also able to downregulate certain oncogenic microbes. Insight into why these microbes are downregulated following exposure to HBV or alcohol, and why the majority of oncogenic microbes are not downregulated, may be critical for understanding whether a pro-tumor liver microbiome could be suppressed or reversed to limit cancer progression.
Highlights
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the second deadliest cancer, affecting over 500,000 people worldwide every year [1]
Raw RNA-sequencing data were downloaded from The Cancer Genome Atlas (TCGA) database for liver hepatocellular carcinoma (LIHC) tumor samples and adjacent normal samples
A potential factor that determines whether a microbe is oncogenic or tumor suppressive is thought to be its effects on modulating the immune system, which could lead to chronic inflammation and an increased risk of cancer, but could lead to immune activation, which is critical for eliminating cancerous cells when they arise
Summary
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the second deadliest cancer, affecting over 500,000 people worldwide every year [1]. One well-established risk factor for HCC is chronic hepatitis B (HBV) infection, which accounts for approximately 50% of all cases [2]. In the absence of diagnostic markers for the early detection of the disease, HBV-related HCC exhibits extremely poor prognosis, with a median survival of less than 16 months [3]. Another well-established risk factor is excessive alcohol use. Multiple epidemiologic and pathologic studies have reported the synergism between alcohol and HBV infection in the context of HCC [5,6,7]. Despite the recent advancements in the knowledge of HCC and cancer in general, the molecular effects of ethanol exposure on the microenvironment and on HCC pathogenesis and progression, and its specific effects in HCC with a chronic viral hepatitis B background, remain poorly characterized
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