Details

Autor(en) / Beteiligte

• Zhang, Ji-Gang
• Zhou, He-Ming
• Zhang, Xue
• Mu, Wan
• Hu, Juan-Ni
• Liu, Gao-Lin
• Li, Qin

Titel

Hypoxic induction of vasculogenic mimicry in hepatocellular carcinoma: role of HIF-1 [alpha], RhoA/ROCK and Rac1/PAK signaling

Ist Teil von

• BMC cancer, 2020-01, Vol.20 (1)

Ort / Verlag

BioMed Central Ltd

Erscheinungsjahr

2020

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Background Vasculogenic mimicry (VM), defined as a capability of aggressive tumor Cells to mimic embryonic vasculogenic networks, caused poor prognosis in hepatocellular carcinoma (HCC). Rho kinases (ROCK), p21-activated kinase (PAK), hypoxia or epithelial-mesenchymal transition (EMT) contributed to the VM potential. However, the details underlying these biological behaviors have not been completely elucidated. Methods Kaplan-Meier analysis was conducted to predict relationship with hypoxia Inducible factor (HIF-1[alpha]), EMT related markers: Vimentin and patient prognosis. CD34/periodic acid-Schiff (PAS) double staining was examined to differentiate VM-positive (VM+) and VM-negative (VM-) samples. Cells were cultured under controlled hypoxic environments (1% O2) or normoxic conditions. The effect of hypoxia on RhoA/ROCK, Rac1/PAK and EMT were evaluated by real time-qPCR and western blot. HIF-1[alpha] small interfering RNA (siRNA), overexpressed or short hairpin RNA (shRNA) of ROCK and kinase inhibitors were used to explore the effect of HIF-1[alpha], RhoA/ROCK, Rac1/PAK and Vimentin on VM. Results HIF-1[alpha] or Vimentin was upregulated in VM+ HCC tissues, compared to non-cancerous tissues (P < 0.01), and patients with high expression of HIF-1[alpha] or Vimentin had worse prognosis (P < 0.001). We showed hypoxia induced RhoA/ROCK and Rac1/PAK signaling transduction, and EMT could be repressed by HIF-1[alpha] siRNA. Notably, RhoA/ROCK or Rac1/PAK stabilized HIF-1[alpha] in hypoxia, whereas HIF-1[alpha] did not significantly altered RhoA/ROCK or Rac1/PAK signaling in hypoxia. Moreover, we found distinct roles of ROCK1, ROCK2 and PAK in regulating Vimentin phosphorylation. Conclusions RhoA/ROCK and Rac/PAK signaling played crucial roles in hypoxia-induced VM via Ser72 and Ser56 Vimentin phosphorylation in HCC. Keywords: HIF-1[alpha], RhoA/ROCK , Rac1/PAK , Vimentin;Vasculogenic mimicry