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[This corrects the article DOI: 10.18632/oncotarget.6461.].
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Current guidelines for lung cancer treatment with EGFR tyrosine kinase inhibitors (TKI) include only patients with mutated EGFR, although some patients with wildtype EGFR (wt-EGFR) have exhibited positive responses to this therapy as well. Biomarkers predicting the benefit from EGFR-TKIs treatment remain to be determined for patients with wild-type EGFR.Here, we report that wt-EGFR overexpression transformed cells in vitro and induced tumorigenesis in vivo in transgenic mouse models. Wt-EGFR driven lung cancer was hypersensitive to TKI treatment in mouse model. Lung cancer patients with high-expression of wt-EGFR showed longer Overall Survival in comparison to low-expression patients after TKI treatment. Our data therefore suggest that treatment with EGFR inhibitors should be extended to include not only patients with mutated EGFR but also a subset of patients with overexpression of wt-EGFR.
Assuntos
Brônquios/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Transformação Celular Neoplásica/patologia , Células Epiteliais/patologia , Receptores ErbB/metabolismo , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , Animais , Biomarcadores Tumorais , Western Blotting , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Receptores ErbB/genética , Feminino , Genótipo , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Células NIH 3T3 , Estadiamento de Neoplasias , Prognóstico , Taxa de SobrevidaRESUMO
PURPOSE: Hepatocellular carcinoma (HCC) is the sixth most common solid tumor worldwide and the third leading cause of cancer-related death. HCC is a particularly serious threat to the Chinese population. Although many molecular alterations are known to be involved in the tumorigenesis of hepatocytes, no systemic survey has examined the somatic mutations in HCC samples from Chinese patients. Our goal was to elucidate somatic mutations in Chinese HCC patients and investigate the possible molecular mechanisms involved in tumorigenesis. EXPERIMENTAL DESIGN: A total of 110 hepatitis B virus (HBV)-positive HCC samples and 46 HBV-negative HCC samples were genotyped for hot-spot mutations in the CSF1R, CTNNB1, KRAS, BRAF, NRAS, ERBB2, MET, PIK3CA, JAK1, and SMO genes. The transcriptomes of the CTNNB1 mutation-positive HCC samples from the HBV-positive patients (CB+ HCC) were compared to adjacent non-cancerous livers, and significantly altered genes were functionally validated in vitro. RESULTS: CTNNB1 mutations accounted for the majority of the mutations detected in our study. A slightly higher mutation rate was found in the HBV-positive patients than in their negative counterparts. A distinct pattern of CTNNB1 mutation was detected in these two populations, and drastic changes at the transcriptomic level were detected in the CB+ tumors compared to adjacent non-cancerous livers. Potential tumor suppressors (FoxA3 and Onecut1) and oncogenes (MAFG and SSX1) were functionally validated. CONCLUSIONS: Our work is the first systemic characterization of oncogenic mutations in HCC samples from Chinese patients. Targeting the Wnt-ß-catenin pathway may represent a valid treatment option for Chinese HCC patients. Our work also suggests that targeting ONECUT1, FOXA3, SSX1, and MAFG may be a valid treatment option for CTNNB1 mutation positive HCC patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Mutação , Proteínas de Neoplasias/biossíntese , Transcriptoma/genética , beta Catenina , Adulto , Idoso , Povo Asiático , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , China , Feminino , Perfilação da Expressão Gênica , Hepatite B/genética , Hepatite B/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Via de Sinalização Wnt/genética , beta Catenina/biossíntese , beta Catenina/genéticaRESUMO
Enterovirus 71 (EV71) is one of the major pathogens that cause hand, foot, and mouth disease outbreaks in young children in the Asia-Pacific region in recent years. Human scavenger receptor class B 2 (SCARB2) is the main cellular receptor for EV71 on target cells. The requirements of the EV71-SCARB2 interaction have not been fully characterized, and it has not been determined whether SCARB2 serves as an uncoating receptor for EV71. Here we compared the efficiency of the receptor from different species including human, horseshoe bat, mouse, and hamster and demonstrated that the residues between 144 and 151 are critical for SCARB2 binding to viral capsid protein VP1 of EV71 and seven residues from the human receptor could convert murine SCARB2, an otherwise inefficient receptor, to an efficient receptor for EV71 viral infection. We also identified that EV71 binds to SCARB2 via a canyon of VP1 around residue Gln-172. Soluble SCARB2 could convert the EV71 virions from 160 S to 135 S particles, indicating that SCARB2 is an uncoating receptor of the virus. The uncoating efficiency of SCARB2 significantly increased in an acidic environment (pH 5.6). These studies elucidated the viral capsid and receptor determinants of enterovirus 71 infection and revealed a possible target for antiviral interventions.