Abstract
BackgroundVasculogenic 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.MethodsKaplan-Meier analysis was conducted to predict relationship with hypoxia Inducible factor (HIF-1α), 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-1α small interfering RNA (siRNA), overexpressed or short hairpin RNA (shRNA) of ROCK and kinase inhibitors were used to explore the effect of HIF-1α, RhoA/ROCK, Rac1/PAK and Vimentin on VM.ResultsHIF-1α or Vimentin was upregulated in VM+ HCC tissues, compared to non-cancerous tissues (P < 0.01), and patients with high expression of HIF-1α 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-1α siRNA. Notably, RhoA/ROCK or Rac1/PAK stabilized HIF-1α in hypoxia, whereas HIF-1α 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.ConclusionsRhoA/ROCK and Rac/PAK signaling played crucial roles in hypoxia-induced VM via Ser72 and Ser56 Vimentin phosphorylation in HCC.
Highlights
Vasculogenic mimicry (VM), defined as a capability of aggressive tumor Cells to mimic embryonic vasculogenic networks, caused poor prognosis in hepatocellular carcinoma (HCC)
Several studies have shown the stimulative effect on hypoxia-inducible factor-1α (HIF-1α) activity, which played a critical role in regulating the adaption of carcinomas to hypoxia [7], Zhang et al BMC Cancer (2020) 20:32 on VM formation [5, 8, 9]
A Kaplan-Meier assay showed that patients who VM+ tended to have a poor prognosis (*P < 0.05; Fig. 1b)
Summary
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. Several studies have shown the stimulative effect on hypoxia-inducible factor-1α (HIF-1α) activity, which played a critical role in regulating the adaption of carcinomas to hypoxia [7], Zhang et al BMC Cancer (2020) 20:32 on VM formation [5, 8, 9]. Given the bulk of hypoxic regions in solid tumors, elucidating links between PAK and HIF-1α in hypoxic cancer cells may further unveil details in mechanisms of cancer development. Our previous report mentioned that ROCK plays an important mediated role in the process of cancer cell VM formation [4]. HIF-1α, ROCK isoforms and PAK seemed to be potential molecular targets for the investigation of VM research
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