Survivin has been considered as a key oncogene in liver carcinogenesis. However, due to the small molecular size, it is so far unsuccessful in developing inhibitors against Survivin. A comprehensive understanding of molecular mechanisms controlled by Survivin may lead to developing novel anti-HCC strategy by targeting its downstream pathways.

Hepatocellular carcinoma (HCC) is a dreaded disease worldwide lacking effective therapies. Recently, a new therapeutic strategy for this disease has been raised by Chinese researchers. In a study, Prof. HUI Lijian’s lab at Institute of Biochemistry and Cell Biology (SIBCB), Shanghai Institutes for Biological Sciences (SIBS) of Chinese Academy of Sciences and co-workers, revealed that inhibitor of apoptosis protein, Survivin, played important roles in HCC development. This work has been published in Hepatology. 

In previous studies, Prof. HUI Lijian’s lab found that Survivin played important roles for the survival of HCC initiating cells (Min, et al, Nature Cell Biology, 2012) and inducible ablation of Survivin in adult liver does not affect liver homeostasis during a long life period (Li, et al, Hepatology, 2013). These data support the notion that Survivin is an ideal target for HCC therapy.

In this study, researchers found that Survivin ablation dramatically suppresses human and mouse HCCs by triggering senescence-associated Tumor Necrosis Factor α (TNFα) and sensitizing HCC cells to TNFα-induced cell death. Combined use of mitotic inhibitor and SMAC mimetic can induce senescence-associated TNFα, enhance TNFα-induced cell death and synergistically eliminate HCC.

They found a near-complete HCC regression upon genetic deletion of Survivin in HCCs. Thorough characterization of Survivin downstream mechanisms led to an unexpected finding of a TNFα-mediated synergistic lethal effect between senescence and apoptosis sensitization on eliminating both senescent and non-senescent HCC cells. Survivin deficiency induces mitosis defect-caused senescence and increases TNFα in HCCs. Moreover, Survivin deletion hypersensitizes both senescent and neighboring non-senescent HCC cells to TNFα-triggered cell death.

Based on these findings, researchers designed and validated a new HCC therapeutic strategy by combination use of mitotic inhibitor and SMAC mimetic to induce mitosis arrest-associated senescence and to enhance TNFα-induced cell death, respectively.

This work was supported by grants from the Ministry of Science and Technology of China, National Natural Science Foundation of China project, Science and Technology Commission of Shanghai Municipality.