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Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and its extremely high mortality rate can be attributed to the lack of suitable biomarkers for early diagnosis, as well as insufficient understanding of HCC heterogeneity and treatment resistance.
Cancer stem cells (CSCs) that are capable of self-renewal and differentiation are considered to be the origin of tumors and are closely related to tumorigenesis, tumor recurrence and metastasis, and treatment resistance. However, we still know little about how to modulate the stem-cell-like characteristics of HCC cells and block the source of tumor malignant forces.
Recently, the latest study jointly completed by Ke Li and Jiandong Jiang from the Institute of Pharmaceutical Biotechnology of the Chinese Academy of Medical Sciences and Jian Yuan from the East Hospital Affiliated to Tongji University was published in the journal Nature Communications, revealing a new mechanism for the occurrence of liver cancer.
They found that SCARB2 drives HCC development by enhancing the transcription factor activity of MYC proteins to maintain the stem-like characteristics of HCC cells. The use of polymyxin B can inhibit the interaction between SCARB2 and MYC, thereby inhibiting the occurrence and metastasis of HCC, and the combination with small molecule targeted drugs is more effective in treating mice[1].
Screenshot of the first page of the paper
First, the research team used CRISPR/Cas9 library screening to find that SCARB2 protein is involved in maintaining the stem-like characteristics of HCC cells. In vitro experiments verified that the levels of cancer stem cell markers such as CD24, EpCAM, CD13 and CD133 in HCC cells with SCARB2 knockout were reduced, and the ability to form spheroids and proliferation was inhibited.
In addition, analysis based on the Human Cancer Genome Atlas (TCGA) showed that SCARB2 levels were up-regulated in HCC tumors at all pathological stages compared with normal liver tissues, which was positively correlated with the levels of cancer stem cell markers. Moreover, high SCARB2 expression is associated with short survival in HCC patients.
The results of HCC mouse model experiments showed that the loss of SCARB2 expression led to a significant decrease in tumor size, liver weight, and the number of pulmonary nodules, prolonged the survival time of mice, and increased sensitivity to the small molecule targeted drug sorafenib. In a mouse model of spontaneous HCC, SCARB2 deletion reduces cancer incidence.
These results suggest that SCARB2 is key to maintaining the stem-cell-like characteristics of HCC cells, thus playing an important role in the occurrence and metastasis of HCC.
SCARB2 deletion reduces tumor growth and metastasis
Further studies have found that SCARB2 drives hepatocellular carcinomagenesis by regulating MYC protein activity.
Specifically, intracellular MYC protein regulates cell growth, differentiation, and apoptosis with transcription factor activity, and its abnormal expression is a necessary part of the process of hepatocyte reprogramming into cancer stem cells. The binding of protease HDAC3 to MYC induces deacetylation of MYC and down-regulates the activity of MYC. SCARB2 can compete with HDAC3 for binding to MYC, thereby increasing the acetylation level of MYC and increasing the activity of MYC transcription factors.
In other words, if we want to crack the anti-cancer technique of SCARB2, we can avoid SCARB2 running to compete with HDAC3 for MYC.
For example, who to find to intervene in the "bad relationship" between SCARB2 and MYC.
The research team first delineated the special domain of SCARB2 binding to MYC, and then screened from 1,317 FDA-approved drugs and found that polymyxin B has a high affinity for this domain of SCARB2 (KD=0.231 μM).
The results of in vitro experiments showed that the addition of polymyxin B could indeed destroy this relationship, and inhibit the colocalization and interaction of SCARB2 and MYC in HCC cells by virtue of its high affinity for binding to SCARB2, thereby reducing the acetylation level and activity of MYC. Consistent with SCARB2 knockout, polymyxin B treatment was able to inhibit the stem-cell-like signature of a variety of HCC cell lines.
Design of Experiments and Mechanisms
In a xenograft mouse model of HCC, polymyxin B alone significantly reduced the ratio of intratumoral cancer stem cells and inhibited tumor growth and metastasis compared with the control group. In addition, polymyxin B can increase the sensitivity of mice to sorafenib, and the therapeutic effect of polymyxin B + sorafenib is more significant when combined.
Polymyxin B treatment showed no significant side effects. Compared with the control group, there was no difference in total body weight and liver weight in HCC mice treated with polymyxin B, and there was no difference in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol (CHO), glucose (GLU) and triglyceride (TG), indicating that the treatment had little effect on liver function.
Effect of polymyxin B and in combination with sorafenib in HCC mice
In conclusion, the research team revealed a novel mechanism by which hepatocellular carcinoma cells maintain stem-like properties and identified SCARB2 as a potential therapeutic target to inhibit tumorigenesis and metastasis.
Polymyxin B is currently an antibiotic used in clinical practice, and few studies have reported its anti-tumor application so far. In this study, the results of mouse experiments highlighted the clinical translational value of polymyxin B in the treatment of hepatocellular carcinoma, and the adverse effects of polymycin B in vivo may be further explored in the future.
Bibliography:
[1]https://www.nature.com/articles/s41467-023-41593-z
The author of this article丨Zhang Aidi