Lysyl oxidase-like 2 as a new poor prognosis marker of squamous cell carcinomas.
Lysyl oxidase-like 2 (Loxl2) interacts with and stabilizes Snai1 transcription factor, promoting epithelial-mesenchymal transition. Either Loxl2 or Snai1 knock-down blocks tumor growth and induces differentiation, but the specific role of each factor in tumor progression is still unknown. Comparison of the gene expression profiles of the squamous cell carcinoma cell line HaCa4 after knocking-down Loxl2 or Snai1 revealed that a subset of epidermal differentiation genes was specifically up-regulated in Loxl2-silenced cells. In agreement, although both Loxl2- and Snai1-knockdown cells showed reduced in vivo invasion, only Loxl2-silenced cells exhibited a skin-like epidermal differentiation program. In addition, we show that expression of Loxl2 and Snai1 correlates with malignant progression in a two-stage mouse skin carcinogenesis model. Furthermore, we found that increased expression of both LOXL2 and SNAI1 correlates with local recurrence in a cohort of 256 human laryngeal squamous cell carcinomas. We describe for the first time that high levels of LOXL2 are associated with decreased overall and disease-free survival in laryngeal squamous cell carcinomas, lung squamous cell carcinoma, and lymph node-negative (N(0)) breast adenocarcinomas. Altogether, our results show that LOXL2 can be used as a new poor prognosis indicator in human squamous cell carcinomas promoting malignant transformation by both SNAI1-dependent and SNAI1-independent pathways.
Peinado
Héctor
H
Departamento de Bioquímica, Instituto de Investigaciones Biomédicas "Alberto Sols" Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Universidad Autónoma de Madrid, Madrid, Spain.
Moreno-Bueno
Gema
G
Hardisson
David
D
Pérez-Gómez
Eduardo
E
Santos
Vanesa
V
Mendiola
Marta
M
de Diego
Juan Ignacio
JI
Nistal
Manuel
M
Quintanilla
Miguel
M
Portillo
Francisco
F
Cano
Amparo
A
D015127:9,10-Dimethyl-1,2-benzanthracene; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007822:Laryngeal Neoplasms / Q000201:enzymology* / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D009924:Organ Culture Techniques; D011379:Prognosis; D034741:RNA, Small Interfering / Q000494:pharmacology; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D000071250:Snail Family Transcription Factors; D015996:Survival Rate; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D014408:Biomarkers, Tumor; D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D015127:9,10-Dimethyl-1,2-benzanthracene; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human