title: Re-expression of the methylated EDNRB gene in oral squamous cell carcinoma attenuates cancer-induced pain.
abstract: Endothelin-1 is a vasoactive peptide that activates both the endothelin A (ET(A)) and endothelin B (ET(B)) receptors, and is secreted in high concentrations in many different cancer environments. Although ET(A) receptor activation has an established nociceptive effect in cancer models, the role of ET(B) receptors on cancer pain is controversial. EDNRB, the gene encoding the ET(B) receptor, has been shown to be hypermethylated and transcriptionally silenced in many different cancers. In this study we demonstrate that EDNRB is heavily methylated in human oral squamous cell carcinoma lesions, which are painful, but not methylated in human oral dysplasia lesions, which are typically not painful. ET(B) mRNA expression is reduced in the human oral squamous cell carcinoma lesions as a consequence of EDNRB hypermethylation. Using a mouse cancer pain model, we show that ET(B) receptor re-expression attenuates cancer-induced pain. These findings identify EDNRB methylation as a novel regulatory mechanism in cancer-induced pain and suggest that demethylation therapy targeted at the cancer microenvironment has the potential to thwart pain-producing mechanisms at the source, thus freeing patients of systemic analgesic toxicity.
authors.affiliation: Department of Oral and Maxillofacial Surgery, New York University, New York, NY, USA Oral and Craniofacial Graduate Program, University of California, San Francisco, San Francisco, CA, USA Department of Oral and Maxillofacial Surgery, University of California, San Francisco, San Francisco, CA, USA Bluestone Center for Clinic Research, New York University, NY, USA.
authors.forename: Chi T
authors.initials: CT
authors.lastname: Viet
authors.forename: Yi
authors.initials: Y
authors.lastname: Ye
authors.forename: Dongmin
authors.initials: D
authors.lastname: Dang
authors.forename: David K
authors.initials: DK
authors.lastname: Lam
authors.forename: Stacy
authors.initials: S
authors.lastname: Achdjian
authors.forename: Jianan
authors.initials: J
authors.lastname: Zhang
authors.forename: Brian L
authors.initials: BL
authors.lastname: Schmidt
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000628:therapy*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics*; D004195:Disease Models, Animal; D005157:Facial Pain / Q000209:etiology* / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics* / Q000628:therapy*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D044023:Receptor, Endothelin B / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D044023:Receptor, Endothelin B