Abstract
In this study, a novel mouse model of hepatocellular carcinoma (HCC) was established by simultaneously knocking out Pten and p53 suppressor genes and overexpressing c-Met and △90-β-catenin proto-oncogenes in the livers of mice via hydrodynamic injection (HDI). The mutations were introduced using the CRISPR/Cas9 and Sleeping Beauty transposon systems. In this way, a primary liver cancer model was established within six weeks. In addition, macrophages expressing arginase-1(Arg1) promoter coupled with firefly luciferase were engineered for bioluminescence imaging (BLI) of the tumor microenvironment. This novel, rapidly-generated model of primary hepatocellular carcinoma can be monitored noninvasively, which can facilitate not only applications of the model, but also the development of new drugs and treatment strategies of HCC.
Highlights
Hepatocellular carcinoma (HCC), a highly prevalent malignancy with over 800,000 cases diagnosed annually worldwide, is the second leading cause of cancer-related deaths [1, 2]
After the plasmids were packed into lentiviruses and transduced into the target cells, gene knockout was confirmed at the predicted site before the proto-spacer adjacent motif (PAM) (Figure 1D)
In order to achieve the knockout of tumor suppressor genes as well as the long-term stable expressions of oncogenes, the Sleeping Beauty (SB) transposon system was amplified with c-Met and △90-bcatenin genes (Figure 1B)
Summary
Hepatocellular carcinoma (HCC), a highly prevalent malignancy with over 800,000 cases diagnosed annually worldwide, is the second leading cause of cancer-related deaths [1, 2]. Diagnosis and therapy of HCC are important for improvement of the patients’ prognosis. HCC is diagnosed by imaging [3] and measuring serum alpha-fetoprotein (AFP) levels [4]. Though serum tumor markers, such as AFP and tumor-associated antigens (TAAs), are engaging alternatives for monitoring and early diagnosis of hepatocellular carcinoma, their sensitivities and specificities remain disappointing. 40% of affected patients are already in the advanced stage of HCC at the time of diagnosis, making surgical treatments impossible. The first-line treatment for advanced HCC is sorafenib, which provides finite clinical benefit [7].
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