Hepatocellular carcinoma (HCC) is the most predominant primary malignancy in the liver. Genotoxic and genetic models have revealed that HCC cells are derived from hepatocytes, but where the critical region for tumor foci emergence is and how this transformation occurs are still unclear. Here, hyperpolyploidization of hepatocytes around the centrilobular (CL) region is demonstrated to be closely linked with the development of HCC cells after diethylnitrosamine treatment. We identify the CL region as a dominant lobule for accumulation of hyperpolyploid hepatocytes and preneoplastic tumor foci formation. We also demonstrate that upregulation of Aurkb plays a critical role in promoting hyperpolyploidization. Increase of AURKB phosphorylation is detected on the midbody during cytokinesis, causing abscission failure and hyperpolyploidization. Pharmacological inhibition of AURKB dramatically reduces nucleus size and tumor foci number surrounding the CL region in diethylnitrosamine-treated liver. Our work reveals an intimate molecular link between pathological hyperpolyploidy of CL hepatocytes and transformation into HCC cells.
Vascular endothelial growth factor receptor 3 (VEGFR-3) supports tumor lymphangiogenesis. It was originally identified as a lymphangiogenic factor expressed in lymphatic endothelial cells. VEGFR-3 was detected in advanced human malignancies and correlated with poor prognosis. Our previous studies show that activation of the VEGF-C/VEGFR-3 axis promotes cancer metastasis and is associated with clinical progression in patients with lung cancer, indicating that VEGFR-3 is a potential target for cancer therapy. In this study, we developed eight peptides targeting VEGFR-3. Two peptides strongly inhibited the kinase activity of VEGFR-3 and suppressed VEGF-C-mediated invasion of cancer cells. Moreover, these peptides abolished VEGF-C-induced drug resistance and tumor initiating cell formation. This study demonstrates the therapeutic potential of VEGFR-3-targeting peptides.
Hepatocellular carcinoma (
HCC
) is a lethal human malignancy and a leading cause of cancer‐related death worldwide. Patients with
HCC
are often diagnosed at an advanced stage, and the prognosis is usually poor. The multikinase inhibitor sorafenib is the first‐line treatment for patients with advanced
HCC
. However, cases of primary or acquired resistance to sorafenib have gradually increased, leading to a predicament in
HCC
therapy. Thus, it is critical to investigate the mechanism underlying sorafenib resistance. Transactivation response element
RNA
‐binding protein 2 (TARBP2) is a multifaceted mi
RNA
biogenesis factor that regulates cancer stem cell (
CSC
) properties. The tumorigenicity and drug resistance of cancer cells are often enhanced due to the acquisition of
CSC
features. However, the role of
TARBP
2 in sorafenib resistance in
HCC
remains unknown. Our results demonstrate that
TARBP
2 is significantly downregulated in sorafenib‐resistant
HCC
cells. The
TARBP
2 protein was destabilized through autophagic–lysosomal proteolysis, thereby stabilizing the expression of the
CSC
marker protein Nanog, which facilitates sorafenib resistance in
HCC
cells. In summary, here we reveal a novel mi
RNA
‐independent role of
TARBP
2 in regulating sorafenib resistance in
HCC
cells.
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