Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the fourth-leading cause of cancer-related deaths worldwide. HCC is refractory to many standard cancer treatments and the prognosis is often poor, highlighting a pressing need to identify biomarkers of aggressiveness and potential targets for future treatments. Kinesin family member 2C (KIF2C) is reported to be highly expressed in several human tumors. Nevertheless, the molecular mechanisms underlying the role of KIF2C in tumor development and progression have not been investigated. In this study, we found that KIF2C expression was significantly upregulated in HCC, and that KIF2C up-regulation was associated with a poor prognosis. Utilizing both gain and loss of function assays, we showed that KIF2C promoted HCC cell proliferation, migration, invasion, and metastasis both in vitro and in vivo. Mechanistically, we identified TBC1D7 as a binding partner of KIF2C, and this interaction disrupts the formation of the TSC complex, resulting in the enhancement of mammalian target of rapamycin complex1 (mTORC1) signal transduction. Additionally, we found that KIF2C is a direct target of the Wnt/β-catenin pathway, and acts as a key factor in mediating the crosstalk between Wnt/β-catenin and mTORC1 signaling. Thus, the results of our study establish a link between Wnt/β-catenin and mTORC1 signaling, which highlights the potential of KIF2C as a therapeutic target for the treatment of HCC.
Highlights
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is currently ranked as the fourthleading cause of cancer-related deaths worldwide (Bray et al, 2018)
We provide experimental evidence showing that Kinesin family member 2C (KIF2C) is upregulated in HCC tissues and that KIF2C upregulation is associated with a more aggressive malignancy and a poor prognosis
We showed that KIF2C strengthened mammalian target of rapamycin complex1 (mTORC1) signaling through its interaction with Tre2-Bub2-Cdc16 1 domain family (TBC1D7), and we provide experimental evidence showing that this interaction results in the disassociation of the TSC complex
Summary
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is currently ranked as the fourthleading cause of cancer-related deaths worldwide (Bray et al, 2018). HCC is a complex and highly heterogeneous cancer that has been associated with various. Despite the plethora of studies on the pathogenesis of HCC in recent decades, the underlying molecular mechanisms are still not fully understood. The prognosis of HCC patients remains dismal, which is in part due to its insidious onset, resulting in a delayed diagnosis, its aggressive malignancy, and its high propensity for metastasis. Many of the standard treatment options for cancer patients, including chemotherapy drugs and radiotherapy, are not highly effective in the treatment of HCC. In the majority of cases, the only curative treatment options include surgical resection and liver transplantation, both of which share a high tumor recurrence rate (Njei et al, 2015). It is of paramount importance to further elucidate the underlying pathogenesis of HCC in order to identify novel therapeutic targets
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