Areca nut components affect COX-2, cyclin B1/cdc25C and keratin expression, PGE2 production in keratinocyte is related to reactive oxygen species, CYP1A1, Src, EGFR and Ras signaling.

[oral submucous fibrosis]

Chewing of betel quid (BQ ) increases the risk of oral cancer and oral submucous fibrosis (OSF ), possibly by BQ-induced toxicity and induction of inflammatory response in oral mucosa .P rimary gingival keratinocytes (GK cells ) were exposed to areca nut (AN ) components with /without inhibitors . Cytotoxicity was measured by 3 -(4 ,5 -dimethyl- thiazol- 2 -yl )-2 ,5 -diphenyl-tetrazolium bromide (MTT ) assay . mRNA and protein expression was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR ) and western blotting . PGE 2 /PGF 2 α production was measured by enzyme-linked immunosorbent assays .Areca nut extract (ANE ) stimulated PGE 2 /PGF 2 α production , and upregulated the expression of cyclooxygenase-2 (COX -2 ), cytochrome P 450 1 A 1 (CYP 1 A 1 ) and hemeoxygenase-1 (HO -1 ), but inhibited expression of keratin 5 /14 , cyclinB 1 and cdc 25 C in GK cells . ANE also activated epidermal growth factor receptor (EGFR ), Src and Ras signaling pathways . ANE-induced COX -2 , keratin 5 , keratin 14 and cdc 25 C expression as well as PGE 2 production were differentially regulated by α-naphthoflavone (a CYP 1 A 1 /1 A 2 inhibitor ), PD 153035 (EGFR inhibitor ), pp 2 (Src inhibitor ), and manumycin A (a Ras inhibitor ). ANE-induced PGE 2 production was suppressed by piper betle leaf (PBL ) extract and hydroxychavicol (two major BQ components ), dicoumarol (aQuinone Oxidoreductase--NQO 1 inhibitor ) and curcumin . ANE-induced cytotoxicity was inhibited by catalase and enhanced by dicoumarol , suggesting that AN components may contribute to the pathogenesis of OSF and oral cancer via induction of aberrant differentiation , cytotoxicity , COX -2 expression , and PGE 2 /PGF 2 α production .CYP 4501 A 1 , reactive oxygen species (ROS ), EGFR , Src and Ras signaling pathways could all play a role in ANE-induced pathogenesis of oral cancer . Addition of PBL into BQ and curcumin consumption could inhibit the ANE-induced inflammatory response .

Diseases
Validation

Diseases presenting "cancer" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

alpha-thalassemia

benign recurrent intrahepatic cholestasis

cadasil

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

coats disease

congenital adrenal hyperplasia

congenital diaphragmatic hernia

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

familial hypocalciuric hypercalcemia

familial mediterranean fever

gm1 gangliosidosis

heparin-induced thrombocytopenia

hereditary cerebral hemorrhage with amyloidosis

hirschsprung disease

hodgkin lymphoma, classical

inclusion body myositis

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

kindler syndrome

lamellar ichthyosis

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

pleomorphic liposarcoma

primary effusion lymphoma

proteus syndrome

pyomyositis

pyruvate dehydrogenase deficiency

severe combined immunodeficiency

sneddon syndrome

systemic capillary leak syndrome

triple a syndrome

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated