Abstract
BackgroundKinesins play important roles in the development and progression of many human cancers. The functions and underlying mechanisms of kinesin family member C1 (KIFC1), a member of the kinesin-14 family, in the pathogenesis of hepatocellular carcinoma (HCC) have not been fully elucidated.MethodsIn this study, 168 HCC samples were first analyzed to examine the association between KIFC1 expression and patient clinicopathological features and prognosis. The role of KIFC1 in HCC cell proliferation and metastasis was investigated both in vivo and in vitro. The upstream regulation and downstream targets of KIFC1 were studied by qRT-PCR, western blotting, coimmunoprecipitation, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays.ResultsKIFC1 was highly expressed in HCC tissues and positively associated with advanced stages and poor prognosis. KIFC1 knockdown suppressed HCC cell proliferation and invasion both in vitro and in vivo. Furthermore, KIFC1 knockdown decreased invadopodia formation and reduced epithelial-mesenchymal transition (EMT). HMGA1, an architectural transcriptional factor, was identified to interact with KIFC1. HMGA1 could bind to the promoters of Stat3, MMP2 and EMT-related genes and promote gene transcription. KIFC1 enhanced HMGA1 transcriptional activity and facilitated HCC proliferation and invasion. Moreover, KIFC1 was activated by TCF-4, and KIFC1 inhibition enhanced HCC cell sensitivity to paclitaxel.ConclusionsOur findings suggest that KIFC1, activated by TCF-4, functions as an oncogene and promotes HCC pathogenesis through regulating HMGA1 transcriptional activity and that KIFC1 is a potential therapeutic target to enhance the paclitaxel sensitivity of HCC.
Highlights
Kinesins play important roles in the development and progression of many human cancers
We investigated the role of kinesin family member C1 (KIFC1) in hepatocellular carcinoma (HCC) pathogenesis and discovered that KIFC1 was highly expressed in both HCC cell lines and clinical samples
KIFC1 is highly expressed in HCC tissue and cancer cell lines The expression of KIFC1 in HCC and adjacent normal tissue samples was tested by both qRT-PCR and western blotting
Summary
Kinesins play important roles in the development and progression of many human cancers. Hepatocellular carcinoma (HCC) accounts for 85–90% of all primary liver cancers. 850,000 new cases are reported each year globally, making it the second leading cause of cancer-related death worldwide. China has approximately 50% of the total number of HCC cases and deaths [1]. HCC has an insidious onset and gradual progression without apparent symptoms and is difficult to diagnose at an early stage. Patients usually present with symptoms at advanced stages. For these patients, there are limited effective therapies. A multikinase inhibitor for HCC first-line therapy, can only increase survival by approximately 3 months. There is great urgency for HCC researchers to find new biomarkers to diagnose HCC at an early stage and competent targets to improve the dismal survival of patients
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