The HGF/c-Met signaling pathway in Hodgkin lymphoma

HGF/c-Met signaling pathway might play a role in the pathogenesis of Hodgkin lymphoma (HL). Co-expression of c-Met and HGF in Hodgkin tumor cells was observed in 11% of the HL patient tissues and HGF/c-Met signaling pathway regulates cell growth and cell cycle progression in Hodgkin cell line L428.
HL is a B-cell neoplasm characterized by a minority of neoplastic cells, which are located within an extensive infiltrate of reactive cells. Activation of the hepatocyte growth factor (HGF)/c-Met signaling pathway has been implicated in the pathophysiology of many cancers, but its role in HL is poorly investigated.
The expression of c-Met and HGF in HL patient tissues was studied by immunohistochemistry. The c-Met expression level was determined in HL cell lines by Western blotting (WB), while HGF mRNA and protein levels were measured by quantitative (q)RT-PCR and ELISA. The effects of SU11274 (a specific c-Met kinase inhibitor) treatment on the activity of the HGF/c-Met signaling pathway in HL cell lines was determined by detection of phosphorylated downstream targets by WB. Effects of SU11274 on cell growth and cell cycle were determined by MTT assay and by flow cytometry with Propidium iodide (PI), respectively in HL cell lines.

C-Met was detected in Hodgkin tumor cells in 55% (26/47) of HL patient tissues. Expression of HGF was detected in Hodgkin tumor cells in 5 c-Met positive and 2 c-Met negative HL patient tissues. C-Met was highly expressed in L428 compared to three other HL cell lines, whereas HGF was highly expressed in KMH2. Detectable levels of phosphorylated c-Met (p-Met) were observed only in L428. Phosphorylation of c-Met, Akt and Erk1/2 were upregulated upon HGF stimulation of L428 cells. This activation could be blocked by inhibiting c-Met activation with SU11274. In functional studies, SU11274 suppressed cell growth in L428. SU11274 promoted G2/M cell cycle arrest after 24h incubation, and induced tetraploidy after 48h in L428 cells. Washing of the cells after induction of G2/M arrest resulted in normal cell cycle progression indicating that the G2/M cell cycle arrest was reversible. Inhibition of PI3K, MEK1/2 and Erk1/2, three downstream targets of the HGF/c-Met signaling pathway, also induced G2/M cell cycle arrest in L428, indicating that these factors are involved in the G2/M cell cycle arrest induced by SU11274.
This study provides a new insight in the pathogenesis of HL and implicates the HGF/c-Met signaling pathway as a potential therapeutic target.

This work is supported by the J.K. de Cock Foundation, and C. Xu has received a Bernouilli bursary.