Neuropilin-1 is involved in regulation of apoptosis and migration of human colon cancer

Abstract

Vascular endothelial growth factor (VEGF) plays critical roles in cancer aggressiveness. We investigated the clinical and biological significance of neuropilin (NP)-1, a member of the VEGF receptor family, in colon carcinoma. We transfected NP-1-specific small interfering RNA (siRNA) into a human colon adenocarcinoma cell line, WiDR, and investigated its effect on proliferation, migration, and apoptosis. We also examined the relationship between clinicopathologic features and NP-1 expression in 146 patients with advanced colorectal carcinoma who had undergone surgery. Inhibition of NP-1 expression in WiDR cells by RNA interference decreased cell migration (no treatment, 143.3/field; mock, 146.8/field; scrambled siRNA, 134.6/field; NP-1 siRNA 79.6/field) and promoted apoptosis (no treatment, 3.52%; scrambled siRNA, 3.80%; NP-1 siRNA, 14.22%), but did not alter cell proliferation. In patients with advanced colorectal carcinoma, those with tumors with high levels of NP-1 staining showed a significantly higher incidence of lymph node (73.0%) or liver (86.2%) metastasis, greater microvessel density (MVD) (60.4/field), greater number of proliferating carcinoma cells (48.6%), and lesser number of apoptotic carcinoma cells (5.70‰) than those with tumors with low levels of NP-1 staining (lymph node, 56.9%; liver, 59.8%; MVD, 47.8/field; proliferating cells, 42.0%; apoptosis, 8.44‰). Survival for patients with tumors with high levels of NP-1 staining was significantly shorter than for those with tumors with low levels of NP-1 staining. Our results suggest that autocrine-NP-1 pathways control the migration and survival of colon carcinoma cells. NP-1 expression may stimulate tumor growth by enhanced angiogenesis and suppression of tumor cell apoptosis, which lead to metastasis and poor prognosis.

Migration-promoting role of VEGF-C and VEGF-C binding receptors in human breast cancer cells

“…NRP-2 can contribute to cell migration in collaboration with VEGFR-2 and VEGFR-3; NRP-2 ligand semaphorin-3F and NRP siRNA both inhibited the response of human microvascular endothelial cells (HMVEC) to VEGF-A and VEGF-C (Favier et al, 2006). The role of NRP-1 in migration was also demonstrated for a human colon adenocarcinoma cell line WiDR, which showed a significant drop in migratory activity after transfection with NRP-1 siRNA (Ochiumi et al, 2006). The principal demonstrated function of a9b1 integrin is acceleration of leucocyte migration, an effect that depends on unique sequences within the a9 cytoplasmic domain (Shang et al, 1999;Young et al, 2001;Chen et al, 2004).…”

“…Another possible reason of this finding is the differential expression of VEGFR-2 in these two cell lines (Figure 2A), since the need for a cooperation between NRPs and VEGFR-2 has been reported for certain NRP actions in other cells. NRP-1 and NRP-2 are non-tyrosine kinase receptors which are believed to transmit intracellular signals in conjunction with coreceptor complexes involving plexin, VEGFR-1, or VEGFR-2 (Ellis, 2006;Guttmann-Raviv et al, 2006;Ochiumi et al, 2006). VEGFR-2 has been reported to interact with NRP-2 and promote the survival and migration of HMVECs (Favier et al, 2006) and its interaction with NRP-1 is needed for migration of human vascular smooth muscle cells (Liu et al, 2005).…”

Overexpression of VEGF189 in breast cancer cells induces apoptosis via NRP1 under stress conditions

“…20,21 NRP1 is expressed at high levels in several tumor cells, where it has been implicated in cell migration and survival. 11,12,[22][23][24][25][26][27] Recently, our group showed that VEGF189 binds to NRP1, 10 in addition to VEGF165. However, the role of VEGF189-NRP1 association in survival has not been elucidated.…”

Neuropilins

“…43 Patients with advanced colorectal carcinoma and high levels of NRP1 staining showed significantly higher incidences of lymph node or liver metastasis and shorter survival than patients with low levels of NRP. 44 In gastrointestinal cancers NRP1 expression correlated with increased invasive growth. 45 NRP2 expression can also correlate with tumor progression.…”