Primary liver cancer is one of the diseases that seriously threaten human health, mainly including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, of which HCC accounts for about 85% of primary liver cancer. HCC has a high incidence and malignancy, with a five-year survival rate of less than 20%. HCC has obvious tumor heterogeneity, such as heterogeneity and cancer stem cell heterogeneity, which is one of the main reasons for its difficulty in early clinical diagnosis, precision treatment and poor prognosis. Since its establishment, the applicant's laboratory has focused on the molecular mechanism of HCC tumor heterogeneity, that is, the key molecular mechanism of different liver cancer subtypes, and the clinical translational application of these mechanisms in the precision diagnosis and treatment of liver cancer (Figure 1)
Our research group has achieved a series of meaningful research results focusing on the heterogeneity of liver cancer and the heterogeneity of cancer stem cells:
●Related achievements: published a total of 57 research papers and applied for 6 patents in international high-level journals, such as first author published papers in N Engl J Med, Hepatology, etc.
●In the past five years (2017-2022), he has published 21 academic papers (10 corresponding authors) and applied for 4 patents (2 authorized, 1 transferred), such as independent corresponding authors published in Gut, Hepatology, Cancer Res, etc. (Figure 1).
●At present, the article has been cited more than 4500 times, which has been unanimously recognized by scholars and experts at home and abroad, such as the research results have been recommended by academic journals, and he has been invited to write review papers and English papers for many important journals at home and abroad (see the following results introduction for details).
Figure 1. Research Directions and Major Innovations (First author and corresponding author)
The main academic contributions, innovations, and their scientific socio-economic value are summarized below:
1) Gender heterogeneity: refers to the incidence and mortality of HCC in men is more than twice that of women worldwide.
It was revealed that the liver-specific enzyme CYP39A1 was significantly more expressed in female liver than in men, while significantly inhibiting the occurrence and development of HCC and weakening the function of HCC sex differences (Gut, 2022, independent communication). This result was immediately recommended as a highlight and review by Nature Review (Nat Rev Gastro Hepat 2022), detailing the findings and scientific significance of this work, arguing that our "study highlights the role of highly expressed cytochrome protein CYP39A1 in women in significantly inhibiting the occurrence and development of HCC" and "the new role of cytochrome protein CYP39A1 in inhibiting the c-Myc pathway". At the same time, the CYP39A1 adeno-associated virus prepared in this project can significantly inhibit the occurrence and development of HCC with high efficiency and non-toxicity (patent 202011304690.1, first applicant). At present, it has cooperated with the company to carry out relevant toxicological and pharmacodynamic studies to prepare for smooth transformation.
miR-26 was found to be a heterogeneous miRNA of both sexes, and it could predict the prognosis and efficacy of interferon therapy with HCC in multiple clinical cohorts, and had important accurate and collaborative diagnostic value in the treatment of interferon after HCC (N Engl J Med 2009, first author; Granted patent US2011/0124521 A1, second applicant). Continuing this work, we continued to reveal in depth the expression silencing mechanism of miR-26 localized in the intron region and its independent transcription mechanism independent of host genes, and the role of its target genes in driving primary cells to obtain dedifferentiation ability (Int J Biol Sci 2017, final communication; Trans Oncol 2021, Common Communications).
2) Heterogeneity of cancer stem cells: HCC cancer stem cell heterogeneity, reflected in the fact that some HCC cells in tumor tissues have the characteristics of cancer stem cells, which are tumorigenic cell populations in HCC; It is also reflected in the existence of multiple types of cancer stem cell populations positive for different markers in HCC, and their molecular regulatory pathways are obviously different.
Our study found the presence of EpCAM+ hepatocellular cancer stem cells in hepatocellular carcinoma, revealing the molecular regulatory pathway of EpCAM+ cancer stem cells and their specific molecular expression profiles that are different from normal hepatic stem cells (Hepatology 2009, first author; Gastroenterology 2009, second author; J Hepatology 2010 in one row; Hepatology 2015, co-corresponding author; Granted patent US2010/0197770 A1, second applicant).
The further in-depth study analyzed the differential molecular expression profiles of multiple types of cancer stem cell-positive liver cancer, and revealed a key self-feedback activation miR-192-5p signaling pathway that can regulate multiple types of cancer stem cells. The relationship between stem characteristics of cancer stem cells and tumor metabolism was revealed, which provided a new understanding of the key metabolic characteristics of HCC cancer stem cells. It also suggests the importance of epigenetic modification regulation on the function of cancer stem cells. These findings provide new insights into the heterogeneity of cancer stem cells, suggesting that miR-192-5p may be an important HCC tumor suppressor gene (Hepatology 2015, I/Co-communication; Cancer Res 2019, Independent Communications; J Exp Clin Cancer Res 2020, Independent Communications), etc.
This series of studies fills the gap in people's comprehensive understanding of the similarities and differences between normal stem cells and cancer stem cells in the liver, and provides a feasible path for specifically targeting the elimination of cancer stem cells, thereby reducing tumor formation, recurrence and metastasis in patients. Due to our in-depth analysis of the heterogeneity of HCC cancer stem cells, our research results have attracted the attention of peer experts and we have been invited to write a review in this field (Cancer Biol Med 2017, common newsletter; Acta Biochim Biophys Sin 2020, Independent Communications; Essays Biochemistry 2022, independent newsletter), and publications (Precision Molecular Pathology of Liver Cancer, Springer, 2017, chapter independent newsletter).
3) Heterogeneity in efficacy: patients with hepatocellular carcinoma have mixed efficacy for transductus arteriosus embolization chemotherapy (commonly known as interventional therapy).
In view of the heterogeneity of interventional treatment, the new molecular mechanism of efficacy resistance miR-125/HIF1A/PDGFB/CD24 of HCC patients was deeply revealed. It was found that among many HCC stem cell populations, CD24 stem cell population was more specifically involved in interventional therapy resistance, and was a key target cell population for potential interventional synergistic therapy. On this basis, for HCC patients who need interventional therapy, a new non-invasive, easy-to-operate feasible method of "pre-selected patients who benefit from treatment" is provided, namely blood testing EPO (Hepatology 2021, independent communication; Authorized patent ZL 202010021315.X, first applicant).
Based on our research and patents, we have registered in the China Clinical Trials Registry for "Clinical Trial of Using Blood Test EPO in Adjuvant TACE Treatment after Early HCC Tumor Resection and Evaluation of the Efficacy of the First TACE Treatment in Patients with Intermediate and Advanced HCC (ChiCTR2100043549, ChiCTR2100045619)", and clinical trials in partner hospitals are currently underway.