Alterations in glucose metabolism proteins responsible for the Warburg effect in esophageal squamous cell carcinoma.
Esophageal squamous cell carcinoma (ESCC) is the most frequent esophageal tumor in the world. ESCC presents late diagnosis, highly aggressive behavior and poor survival. Changes in tumor cell energy metabolism appear to have a prominent role in malignant transformation. Tumor cells consume glucose avidly and produce lactic acid, even under normoxia. Among the factors that may contribute to the stimulation of glycolysis in tumor cells, there are changes in the glycolytic pathway enzymes such as: pyruvate kinase M1 and M2 (PKM2 and PKM1), hexokinase II (HKII), glucose transporter isoform 1 (GLUT-1), and transcription factor induced by hypoxia (HIF1α), responsible for the transcription of proteins cited. The objective of this study is to evaluate the alterations of these proteins and their association with clinicopathological data in ESCC. We performed immunohistochemistry to determine HIF-1α, GLUT-1, PKM1, PKM2, HK2 and Ki67-expression in ESCC patients and controls. Also, we used RT-qPCR to evaluated mRNA expression of GLUT-1 in esophageal mucosa of individuals without cancer, but are alcohol drinkers and tobacco smokers. Our results showed the exclusively expression of GLUT-1 in tumors cells and dysplastic samples. We also observed a compartmentalization of the expression of PKM1 and PKM2 in relation to tumor cells and stroma associated to tumor areas. All of the proteins evaluated, excepted GLUT-1, were frequently detected in normal mucosa. No correlations between clinicopathological features and protein expressions were observed. GLUT-1 expression appears in initial tumor lesions and is maintained through ESCC evolution. We reported for the first time PKM1 staining in normal esophagus and ESCC, being mostly present in more differentiated cells.
Laboratorio de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil 4365, Manguinhos, Rio de Janeiro, Rio de Janeiro CEP: 21045-900, Brazil. Electronic address: barreto.ester@gmail.com.
Ester
E
de Andrade Barreto
Programa de Carcinogênese Molecular, Instituto Nacional de Câncer José Alencar Gomes da Silva, Coordenação de Pesquisa, Rua André Cavalcanti, 37 - 6° andar, Bairro de Fátima, Rio de Janeiro, Rio de Janeiro CEP: 20231-050, Brazil. Electronic address: pthiagoss@gmail.com.
Paulo Thiago
PT
de Souza Santos
Programa de Carcinogênese Molecular, Instituto Nacional de Câncer José Alencar Gomes da Silva, Coordenação de Pesquisa, Rua André Cavalcanti, 37 - 6° andar, Bairro de Fátima, Rio de Janeiro, Rio de Janeiro CEP: 20231-050, Brazil. Electronic address: abergmann@inca.gov.br.
Anke
A
Bergmann
Divisão de Patologia, Instituto Nacional de Câncer José Alencar Gomes da Silva, Rua Cordeiro da Graça 156, Santo Cristo, Rio de Janeiro, Rio de Janeiro CEP: 20230-240, Brazil. Electronic address: imartins@inca.gov.br.
Ivanir Martins
IM
de Oliveira
Divisão de Patologia, Instituto Nacional de Câncer José Alencar Gomes da Silva, Rua Cordeiro da Graça 156, Santo Cristo, Rio de Janeiro, Rio de Janeiro CEP: 20230-240, Brazil. Electronic address: lwernersbach@inca.gov.br.
Luciana
L
Wernersbach Pinto
Divisão de Patologia, Instituto Nacional de Câncer José Alencar Gomes da Silva, Rua Cordeiro da Graça 156, Santo Cristo, Rio de Janeiro, Rio de Janeiro CEP: 20230-240, Brazil. Electronic address: taniacmblanco@yahoo.com.br.
Tania
T
Blanco
Departamento de Bioquímica, IBRAG, UERJ, Av. 28 de Setembro, 87 fundos, 4° Andar, Rio de Janeiro, Rio de Janeiro CEP: 20551-013, Brazil. Electronic address: anartc@gmail.com.
Ana
A
Rossini
Hospital de Clínicas de Porto Alegre, PPG-Ciências Cirúrgicas-Famed, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2400 2o andar, Santana, Porto Alegre, Rio Grande do Sul CEP: 90035-903, Brazil. Electronic address: cdkruel@yahoo.com.br.
Cleber Dario
CD
Pinto Kruel
Departamento de Bioquímica, IBRAG, UERJ, Av. 28 de Setembro, 87 fundos, 4° Andar, Rio de Janeiro, Rio de Janeiro CEP: 20551-013, Brazil. Electronic address: albano@uerj.br.
Rodolpho
R
Mattos Albano
Programa de Carcinogênese Molecular, Instituto Nacional de Câncer José Alencar Gomes da Silva, Coordenação de Pesquisa, Rua André Cavalcanti, 37 - 6° andar, Bairro de Fátima, Rio de Janeiro, Rio de Janeiro CEP: 20231-050, Brazil. Electronic address: lfrpinto@inca.gov.br.
Luis Felipe
LF
Ribeiro Pinto
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004848:Epithelium / Q000201:enzymology / Q000473:pathology; D004938:Esophageal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000201:enzymology / Q000473:pathology; D011770:Pyruvate Kinase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D059016:Tumor Microenvironment; D055815:Young Adult
D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; D012333:RNA, Messenger; C495677:SLC2A1 protein, human; D006593:Hexokinase; D011770:Pyruvate Kinase; D005947:Glucose
Esophageal cancer; GLUT-1; HIF-1α; Hexokinase 2; Pyruvate kinase M2; Warburg effect