# Bile acid accumulation induced by miR-122 deficiency in liver parenchyma promotes cancer cell growth in hepatocellular carcinoma

## TL;DR

Low levels of miR-122 in liver cells increase bile acids, which promote liver cancer growth, suggesting new treatment targets.

## Contribution

Identifies miR-122 deficiency as a driver of bile acid accumulation that promotes hepatocellular carcinoma.

## Key findings

- miR-122 deficiency in hepatocytes increases bile acid levels and promotes liver tumor growth.
- miR-122 inhibits cancer cell proliferation by targeting the bile acid synthesis gene HSD3B7.
- Lower miR-122 in HCC patients correlates with higher bile acids and worse survival.

## Abstract

Liver is the central player in maintaining metabolic homeostasis of bile acids (BAs), but how BA is tightly controlled is still largely unknown, and the role of BAs in the development of hepatocellular carcinoma (HCC) remains controversial. Here, we discovered that elevated hepatic BAs were associated with miR-122 downregulation during liver regeneration, steatosis, and fibrosis. In vivo mouse models showed that miR-122 deficiency of liver parenchymal cells (hepatocytes) in paracancerous tissues resulted in significantly increased BA levels and altered hepatic BA spectrum, thus promoting liver tumor burden, which could be abated by administration of BA sequestrant. Mechanistically, miR-122 attenuated BA production by directly targeting BA synthesis gene HSD3B7, thereby inhibiting cancer cell proliferation and HCC growth. Overexpression of HSD3B7 in hepatocytes abolished the inhibitory effect of intrahepatic delivery of miR-122 on cancer cell proliferation in c-Myc/sgTP53-induced HCC model. Consistently, lower miR-122 was associated with elevated levels of BA and HSD3B7 protein in paracancerous tissues from HCC patients and also associated with worse overall survival of HCC patients. These findings provide novel insights into the roles of miR-122-mediated BA regulatory network of liver parenchymal cells of tumor microenvironment during HCC progression, which may provide attractive therapeutic targets for HCC.

The control of BA homeostasis is unclear, and its role in HCC development remains controversial. Zhu and colleagues demonstrate that miR-122 deficiency in hepatocytes induces BA production by directly upregulating HSD3B7, thereby facilitating cancer cell proliferation and HCC growth. Their findings identify miR-122-HSD3B7-BAs axis as potential therapeutic targets for HCC.