Lipocalin 2 prevents oral cancer metastasis through carbonic anhydrase IX inhibition and is associated with favourable prognosis

Abstract

Lipocalin 2 (LCN2), a secreted glycoprotein, is up- or downregulated in different human cancers. At present, the functional role of LCN2 in the progression of oral squamous cell carcinoma (OSCC), which accounts for most head and neck cancers, remains poorly understood, particularly with respect to its involvement in invasion and metastasis. In this study, we observed that LCN2 expression decreased in patients with OSCC and lymph node metastasis compared with that in patients without metastasis. A higher LCN2 expression correlated with the survival of patients with OSCC. Furthermore, LCN2 overexpression in OSCC cells reduced in vitro migration and invasion and in vivo metastasis, whereas its silencing induced an increase in cell motility. Mechanistically, LCN2 inhibited the cell motility of OSCC cells through hypoxia-inducible factor (HIF)-1α-dependent transcriptional inhibition of the carbonic anhydrase IX (CAIX). CAIX overexpression relieved the migration inhibition imposed by LCN2 overexpression in OSCC cells. Moreover, a microRNA (miR) analysis revealed that LCN2 can suppress CAIX expression and cell migration through miR-4505 induction. Examination of tumour tissues from patients with OSCC and OSCC-transplanted mice revealed an inverse correlation between LCN2 and CAIX expression. Furthermore, patients with LCN2(strong)/CAIX(weak) revealed the lowest frequency of lymph node metastasis and the longest survival. Our findings suggest that LCN2 suppresses tumour metastasis by targeting the transcriptional and post-transcriptional regulation of CAIX in OSCC cells. LCN2 overexpression may be a novel OSCC treatment strategy and a useful biomarker for predicting OSCC progression.

MMP-11 promoted the oral cancer migration and FAK/Src activation

“…TW2.6 cells (5 × 10 4 cells/well) were plated in 6 cm petri dishes for 24 h and wounds were produced by manually scratching with a 200 μL pipette tip as described previously [7]. Images were recorded at indicated times after treatment using a phase-contrast microscope (×100).…”

“…For patients with advanced diseases or pathologic risk factors, adjuvant radiotherapy and/or chemotherapy are also parts of the standard treatments [5]. Despite ongoing advances in the surgical techniques and adjuvant therapies, the 5-year overall survival rate remains unfavorable in a considerable portion of OSCC patients because invasion of the neighboring tissues and metastasis to the neck lymph nodes are common [6, 7]. Therefore, identifying new biomarkers that can predict the risk of OSCC progression, especially local invasion and lymph node metastasis, is mandatory to improve the treatment of this deadly disease.…”

Functional genetic variant in the Kozak sequence of WW domain-containing oxidoreductase (WWOX) gene is associated with oral cancer risk

“…Both cell lines maintained in DMEM/F12 supplemented with 10% FBS, 400 ng/ml hydrocortisone and 0.1 mM non-essential amino acids (NEAA; Life Technologies). OECM-1 cells were obtained from Dr Meng's group where the cell line is originally established and authenticated and maintained in RPMI (Gibco) supplemented with 10% FBS [49]. All the cells were cultured and maintained at 37 °C in a 5% CO 2 and 95% air atmosphere.…”

Levels of neutrophil gelatinase-assosciated lipocalin in patients with head and neck squamous cell carcinoma in Indian population from Haryana state

“…Levels of lipocalin 2 is upregulated or downregulated in different cancers, i.e ., lung, colon, pancreas, breast, prostate, etc [4,6-8]. But studies are scarce in head and neck carcinoma particularly with respect to its involvement in invasion and metastasis.…”