On February 28, 2019, the proteome research results of early hepatocellular carcinoma completed by academician He Fuchu's team, professor Qian Xiaohong's team and academician Fan Jia's team from Zhongshan Hospital, Fudan University were published in Nature. The paper described the proteome expression profile and phosphorylated proteome profile of early hepatocellular carcinoma for the first time.
Due to poor prognosis, high mortality and difficulty in early diagnosis, liver cancer is often referred to as "the king of cancers" (generally considered as pancreatic cancer). Liver cancer is a general term for various histologically different types of primary liver tumors, including hepatocellular carcinoma, intrahepatic cholangiocarcinoma, hepatoblastoma and biliary cystadenocarcinoma. Among them, hepatocellular carcinoma (HCC) accounts for the majority and about 90% of primary hepatocellular carcinoma.
China is a country with large number of liver diseases and liver cancer patients. According to statistics, liver cancer occurs in about 700,000 people around the world every year, more than 350,000 of which are in China. Although surgery may be effective at early stage, the 5-year overall survival rate is only 50-70%. For this group of early liver cancer patients with poor prognosis, there is still a lack of effective targeted therapy. Therefore, based on China's national conditions, it is of great practical significance to find new targets for accurate treatment of liver cancer.
In this study, according to the proteomic data of 101 cases of early hepatocellular carcinoma patients with cancer tissue and paired para-carcinoma tissue samples, the patients with early hepatocellular carcinoma clinically considered at present were divided into three proteomic subtypes (S-I, S-II, S-III). Patients with different subtypes have different prognostic characteristics, and different treatment strategies should be adopted after surgery. Among them, patients with hepatocellular carcinoma of S-I subtype only need surgery to prevent overtreatment. Patients with S-II subtype of hepatocellular carcinoma need surgery and other adjuvant treatments. The S-III subtype patients with highest postoperative recurrence and metastasis risk account for 30% of the enrolled population, which can be regarded as the last "tough bone".
The researchers first identified a reprogramming of cholesterol metabolic pathways in proteomic data from the S-III subtype. In case of no obvious rise of blood cholesterol concentration of early liver cancer patients, intracellular cholesterol steady-state related key proteins, in addition to known as the key enzyme HMGCR of mevalonate pathway closely associated with tumor, and even more key proteins, including the key proteins of bearing LDL cholesterol intake (LDLR), intracellular transport (NPC1), the esterification (SOAT1) and bile acid metabolism (CYP7A1) and the transcription factor regulating cholesterol steady state (SCAP, SREBF2), were significantly raised in liver cancer cells, shows that cholesterol is unstable in the liver cancer cells.
Subsequently, the team found that the expression level of Sterol o-acyltransferase 1 (SOAT1), which is responsible for the conversion of cholesterol into cholesterol esters, was positively correlated with the poor prognosis of liver cancer patients. The team further evidenced that knocking down SOAT1 gene expression in a series of hepatoma cell lines or treating with its small molecule inhibitors can significantly inhibit the extracellular cholesterol intake, thereby reducing the cytoplasm membrane cholesterol level, which makes the abundance of star molecule integrin family closely relating to the development of tumor in cell membrane significantly lower, thus inhibiting tumor cell proliferation and migration.
Then, the team demonstrated that avasimibe, a small molecule inhibitor of SOAT1, showed good anti-tumor effect in the human tumor xenograft (PDX) model of liver cancer patients, which indicated that avasimibe was expected to be a targeted therapy for hepatocellular carcinoma patients with poor prognosis. In the end, the team was surprised to find that SOAT1 protein expression level in thyroid cancer, head and neck cancer, stomach cancer, kidney cancer and prostate cancer is closely related to poor prognosis of patients，thus pointing out that the instability of cholesterol metabolism and the tumor promoting mechanism of SOAT1 is probably not particular in liver cancer, but a common mechanism of a large number of malignant tumors. Therefore, "targeting SOAT1 may provide a new treatment strategy for more types of tumor patients ".