RESUMO
Guilu Erxian Jiao (GEJ) is a commonly used nutritional supplement due to its rich content of amino acids. It is also a traditional herbal medicine for improving degenerative joint. This study aimed to investigate the effect and mechanism of GEJ water extract (GEJ-WE) on skeletal muscle in C2C12 myotubes and C57BL/6J mice. Analysis of GEJ-WE were performed by high-performance liquid chromatography fingerprinting with chemical standards. Protein expression, mRNA level, glycogen content, mitochondria activity and ATP level were evaluated by western blots, real-time PCR, PAS staining, MTT and ATP bioluminescence assay, respectively. Skeletal muscle strength was evaluated by grip strength. Skeletal muscle volume, mass and fiber types were evaluated by micro computed tomography, histological analysis and immunofluorescence staining, respectively. Motor function was evaluated by rotarod performance and locomotor activity. In C2C12 myotubes, GEJ-WE significantly enhanced myogenic differentiation and myotube growth, protein synthesis signaling IGF-1/IGF-1R/IRS-1/Akt, Glut4 translocation, glycogen content, mitochondrial biogenesis signaling PGC-1α/NRF1/TFAM, mitochondrial activity and ATP production. However, IGF-1R antagonist AG1024 and PI3K inhibitor wortmannin reduced GEJ-WE-induced protein expression of MyHC, p-Akt, p-mTOR and p-GSK-3ß, Glut4 translocation and glycogen content. In C57BL/6J mice, GEJ-WE not only upregulated protein synthesis and mitochondrial biogenesis signaling, but it also increased muscle volume, relative muscle weight, cross-sectional area of myofibers, glycogen content and transition of fast-to-slow type fibers of skeletal muscles. Moreover, GEJ-WE enhanced grip strength and motor activity of mice. In conclusion, the upregulation of protein synthesis, myogenic differentiation, glucose homeostasis, mitochondrial biogenesis and slow-twitch fibers contributes to the mechanisms of GEJ-WE on the enhancement of skeletal muscle mass and motor function.
Assuntos
Biogênese de Organelas , Fosfatidilinositol 3-Quinases , Animais , Camundongos , Camundongos Endogâmicos C57BL , Glicogênio Sintase Quinase 3 beta , Proteínas Proto-Oncogênicas c-akt , Microtomografia por Raio-X , Músculo Esquelético , Homeostase , Glucose , Trifosfato de AdenosinaRESUMO
BACKGROUND AND PURPOSE: Increasing evidence suggests systemic inflammation-caused skeletal muscle atrophy as a major clinical feature of cachexia. Triptolide obtained from Tripterygium wilfordii Hook F possesses potent anti-inflammatory and immunosuppressive effects. The present study aims to evaluate the protective effects and molecular mechanisms of triptolide on inflammation-induced skeletal muscle atrophy. EXPERIMENTAL APPROACH: The effects of triptolide on skeletal muscle atrophy were investigated in LPS-treated C2C12 myotubes and C57BL/6 mice. Protein expressions and mRNA levels were analysed by western blot and qPCR, respectively. Skeletal muscle mass, volume and strength were measured by histological analysis, micro-CT and grip strength, respectively. Locomotor activity was measured using the open field test. KEY RESULTS: Triptolide (10-100 fM) up-regulated protein synthesis signals (IGF-1/p-IGF-1R/IRS-1/p-Akt/p-mTOR) and down-regulated protein degradation signal atrogin-1 in C2C12 myotubes. In LPS (100 ng·ml-1 )-treated C2C12 myotubes, triptolide up-regulated MyHC, IGF-1, p-IGF-1R, IRS-1 and p-Akt. Triptolide also down-regulated ubiquitin-proteasome molecules (n-FoxO3a/atrogin-1/MuRF1), proteasome activity, autophagy-lysosomal molecules (LC3-II/LC3-I and Bnip3) and inflammatory mediators (NF-κB, Cox-2, NLRP3, IL-1ß and TNF-α). However, AG1024, an IGF-1R inhibitor, suppressed triptolide-mediated effects on MyHC, myotube diameter, MuRF1 and p62 in LPS-treated C2C12 myotubes. In LPS (1 mg·kg-1 , i.p.)-challenged mice, triptolide (5 and 20 µg·kg-1 ·day-1 , i.p.) decreased plasma TNF-α levels and it increased skeletal muscle volume, cross-sectional area of myofibers, weights of the gastrocnemius and tibialis anterior muscles, forelimb grip strength and locomotion. CONCLUSIONS AND IMPLICATIONS: These findings reveal that triptolide prevented LPS-induced inflammation and skeletal muscle atrophy and have implications for the discovery of novel agents for preventing muscle wasting.
Assuntos
NF-kappa B , Fator de Necrose Tumoral alfa , Animais , Diterpenos , Compostos de Epóxi , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas , Músculo Esquelético/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/prevenção & controle , FenantrenosRESUMO
Kynurenic acid (KYNA, 4-oxoquinoline-2-carboxylic acid), an intermediate of the tryptophan metabolism, has been recognized to exert different neuroactive actions; however, the need of how it or its aminoalkylated amide derivative N-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-oxo-1,4-dihydroquinoline-2-carboxamide (KYNA-A4) exerts any effects on ion currents in excitable cells remains largely unmet. In this study, the investigations of how KYNA and other structurally similar KYNA derivatives have any adjustments on different ionic currents in pituitary GH3 cells and hippocampal mHippoE-14 neurons were performed by patch-clamp technique. KYNA or KYNA-A4 increased the amplitude of M-type K+ current (IK(M)) and concomitantly enhanced the activation time course of the current. The EC50 value required for KYNA- or KYNA-A4 -stimulated IK(M) was yielded to be 18.1 or 6.4 µM, respectively. The presence of KYNA or KYNA-A4 shifted the relationship of normalized IK(M)-conductance versus membrane potential to more depolarized potential with no change in the gating charge of the current. The voltage-dependent hysteretic area of IK(M) elicited by long-lasting triangular ramp pulse was observed in GH3 cells and that was increased during exposure to KYNA or KYNA-A4. In cell-attached current recordings, addition of KYNA raised the open probability of M-type K+ channels, along with increased mean open time of the channel. Cell exposure to KYNA or KYNA-A4 mildly inhibited delayed-rectifying K+ current; however, neither erg-mediated K+ current, hyperpolarization-activated cation current, nor voltage-gated Na+ current in GH3 cells was changed by KYNA or KYNA-A4. Under whole-cell, current-clamp recordings, exposure to KYNA or KYNA-A4 diminished the frequency of spontaneous action potentials; moreover, their reduction in firing frequency was attenuated by linopirdine, yet not by iberiotoxin or apamin. In hippocampal mHippoE-14 neurons, the addition of KYNA also increased the IK(M) amplitude effectively. Taken together, the actions presented herein would be one of the noticeable mechanisms through which they modulate functional activities of excitable cells occurring in vivo.
Assuntos
Hipocampo/fisiologia , Canais de Potássio KCNQ/efeitos dos fármacos , Ácido Cinurênico/farmacologia , Animais , Apamina/farmacologia , Linhagem Celular , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Indóis/farmacologia , Ácido Cinurênico/química , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Técnicas de Patch-Clamp , Peptídeos/farmacologia , Piridinas/farmacologia , RatosRESUMO
The TGF-ß type III receptor (TGFBR3) is an essential constituent of the TGF-ß signaling. In this study, we observed a down-regulation of TGFBR3 in oral cancer, a subtype of head and neck cancer (HNC), and patients with low TGFBR3 had poor clinical outcomes. Ectopic expression of TGFBR3 decreased migration and invasion of oral cancer cells and lymph node metastasis of tumors, whereas depletion of TGFBR3 had the opposite effect. In SMAD4-positive OC-2 oral cancer cells, TGFBR3-mediated suppression requires both of its cytoplasmic interacting partners ARRB2 and GIPC1. We demonstrated that TGFBR3 induces the abundance of secreted angiogenin (ANG), a known pro-angiogenic factor, and ANG is essential and sufficient to mediate TGFBR3-dependent inhibition of migration and invasion of oral cancer cells. Notably, in SMAD4-deficient CAL-27 oral cancer cells, only GIPC1 is essential for TGFBR3-induced suppressive activity. Accordingly, HNC patients with low expressions of both TGFBR3 and GIPC1 had the poorest overall survival. In summary, we conclude that TGFBR3 is as a tumor suppressor via SMAD4-dependent and -independent manner in both tumor and stromal cells during oral carcinogenesis. Our study should facilitate the possibility of using TGFBR3-mediated tumor suppression for HNC treatment.
RESUMO
Oral cancer, a subtype of head and neck cancer, is characterized by increased infiltrating regulatory T cells (Treg); however, the pathological significance of the increase in Tregs in disease prognosis and progression and their underlying mechanism remain unestablished. C-C motif chemokine ligand 22 (CCL22) has been implicated in the recruitment of Tregs. We used RT-qPCR to determine CCL22 mRNA expression in clinical specimens and cultured cells. Loss-of-function and gain-of-function studies were carried out to analyze the effects of CCL22 modulations on cell proliferation, migration, invasion, and tumorigenesis and the mechanism involved in the deregulation of CCL22. In oral cancer specimens, CCL22 mRNA was upregulated. The increase was not only associated with reduced disease-free survival but also strongly correlated with an increase in FOXP3 mRNA, a master regulator of Treg development and functions. Silencing CCL22 expression reduced cell proliferation, migration, and invasion, whereas ectopic overexpression showed opposite effects. Manipulation of CCL22 expression in cancer cells altered tumorigenesis in both immune-compromised and -competent mice, supporting both autonomous and non-autonomous actions of CCL22. Release of interleukin 1ß (IL-1ß) from cancer-associated fibroblasts (CAF) induces CCL22 mRNA expression in oral cancer cells by activating transcription factor nuclear factor kappa B (NF-κB). Our data support a model in which CAF-derived IL-1ß, CCL22, and its receptor CCR4 foster a protumor environment by promoting cell transformation and Treg infiltration. Intervention of the IL-1ß-CCL22-CCR4 signaling axis may offer a novel therapeutic strategy for oral cancer treatment.
Assuntos
Fibroblastos Associados a Câncer/metabolismo , Quimiocina CCL22/metabolismo , Interleucina-1beta/metabolismo , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Fibroblastos Associados a Câncer/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/patologia , Quimiocina CCL22/genética , Intervalo Livre de Doença , Feminino , Seguimentos , Fatores de Transcrição Forkhead/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Interleucina-1beta/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Mucosa Bucal/patologia , Mucosa Bucal/cirurgia , Neoplasias Bucais/imunologia , Neoplasias Bucais/mortalidade , Neoplasias Bucais/cirurgia , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/patologia , Prognóstico , RNA Interferente Pequeno/metabolismo , Receptores CCR4/metabolismo , Transdução de Sinais/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Análise de Sobrevida , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The S100A2 protein is an important regulator of keratinocyte differentiation, but its role in wound healing remains unknown. We establish epithelial-specific S100A2 transgenic (TG) mice and study its role in wound repair using punch biopsy wounding assays. In line with the observed increase in proliferation and migration of S100A2-depleted human keratinocytes, mice expressing human S100A2 exhibit delayed cutaneous wound repair. This was accompanied by the reduction of re-epithelialization as well as a slow, attenuated response of Mcp1, Il6, Il1ß, Cox2, and Tnf mRNA expression in the early phase. We also observed delayed Vegfa mRNA induction, a delayed enhancement of the Tgfß1-mediated alpha smooth muscle actin (α-Sma) axis and a differential expression of collagen type 1 and 3. The stress-activated p53 tumor suppressor protein plays an important role in cutaneous wound healing and is an S100A2 inducer. Notably, S100A2 complexes with p53, potentiates p53-mediated transcription and increases p53 expression both transcriptionally and posttranscriptionally. Consistent with a role of p53 in repressing NF-κB-mediated transcriptional activation, S100A2 enhanced p53-mediated promoter suppression of Cox2, an early inducible NF-κB target gene upon wound injury. Our study thus supports a model in which the p53-S100A2 positive feedback loop regulates wound repair process.
Assuntos
Fatores Quimiotáticos/metabolismo , Retroalimentação Fisiológica , Reepitelização , Proteínas S100/metabolismo , Pele/citologia , Proteína Supressora de Tumor p53/metabolismo , Cicatrização , Actinas/metabolismo , Animais , Movimento Celular , Proliferação de Células , Fatores Quimiotáticos/genética , Colágeno/metabolismo , Ciclo-Oxigenase 2/genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Humanos , Queratinócitos/citologia , Masculino , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas S100/genética , Pele/metabolismo , Transcrição Gênica , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND: Deep burn wounds have a high tendency to form hypertrophic scars. Previously, we found that angiogenin promoted neovascularization during deep burn wound healing. However, the association between angiogenin and scar formation is unclear. METHODS: We obtained human burn scar tissues from patients who underwent scar surgery and examined the role of angiogenin in scar tissues and determined its effects in scar fibroblasts and on transforming growth factor ß1 (TGF-ß1) secretion. RESULTS: Our results showed an inverse correlation between angiogenin expression and scar severity. Next, we examined the effects of angiogenin in scar fibroblasts. We found that angiogenin was persistently expressed in human scar fibroblasts and that angiogenin expression significantly increased with time in the culture medium of scar fibroblasts. Treatment of scar fibroblasts with recombinant angiogenin significantly decreased their proliferation and TGF-ß1 secretion. Moreover, angiogenin inhibited TGF-ß1-mediated Smad2 signaling pathway. CONCLUSION: Our data suggest a negative role of angiogenin in fibroblast proliferation via TGF-ß1-mediated Smad2 signaling pathway.
Assuntos
Queimaduras/patologia , Cicatriz Hipertrófica/metabolismo , Ribonuclease Pancreático/metabolismo , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Biomarcadores/metabolismo , Queimaduras/complicações , Proliferação de Células , Células Cultivadas , Cicatriz Hipertrófica/etiologia , Cicatriz Hipertrófica/patologia , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Técnicas In Vitro , Escala de Gravidade do Ferimento , Masculino , Sensibilidade e Especificidade , Cicatrização/fisiologiaRESUMO
Hyaluronan (HA) is a major extracellular matrix component. However, its role and mediation in oral cancer remains elusive. Hyaluronan synthase 3 (HAS3), involved in pro-inflammatory short chain HA synthesis, was the predominant synthase in oral cancer cells and tissues. HAS3 overexpression significantly increased oral cancer cell migration, invasion and xenograft tumorigenesis accompanied with the increased expression of tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein 1 (MCP-1). Conversely, HAS3 depletion abrogated HAS3-mediated stimulation. HAS3 induced oncogenic actions partly through activating EGFR-SRC signaling. HAS3-derived HA release into extracellular milieu enhanced transendothelial monocyte migration and MCP-1 expression, which was attenuated by anti-HAS3 antibodies or a HAS inhibitor, 4-Methylumbelliferone (4-MU). The NF-κB-binding site III at -1692 to -1682 bp upstream from the transcript 1 start site in HAS3 proximal promoter was the most responsive to TNF-α-stimulated transcription. ChIP-qPCR analysis confirmed the highest NF-κB-p65 enrichment on site III. Increased HAS3 mRNA expression was negatively correlated with the overall survival of oral cancer patients. A concomitant increase of TNF-α, a stimulus for HAS3 expression, with HAS3 expression was not only associated with lymph node metastasis but also negated clinical outcome. Together, HAS3 and TNF-α formed an inter-regulation loop to enhance tumorigenesis in oral cancer.
Assuntos
Regulação Neoplásica da Expressão Gênica , Glucuronosiltransferase/genética , Neoplasias Bucais/genética , Fator de Necrose Tumoral alfa/genética , Animais , Western Blotting , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Feminino , Glucuronosiltransferase/metabolismo , Humanos , Hialuronan Sintases , Ácido Hialurônico/metabolismo , Estimativa de Kaplan-Meier , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Heterólogo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Growth differentiation factor-10 (GDF10), commonly referred as BMP3b, is a member of the transforming growth factor-ß (TGF-ß) superfamily. GDF10/BMP3b has been considered as a tumor suppressor, however, little is known about the molecular mechanism of its roles in tumor suppression in oral cancer. Clinical significance of GDF10 downregulation in oral squamous cell carcinoma (OSCC) was evaluated using three independent cohorts of OSCC patients. The molecular mechanisms of GDF10 in the suppression of cell survival, cell migration/invasion and epithelial-mesenchymal transition (EMT) were investigated by using oral cancer cell lines. The present study shows that GDF10 is downregulated during oral carcinogenesis, and GDF10 expression is also an independent risk factor for overall survival of OSCC patients. Overexpression of GDF10 attenuates cell proliferation, transformation, migration/invasion, and EMT. GDF10-inhibited EMT is mediated by ERK signaling but not by typical TGF-ß signaling. In addition, overexpression of GDF10 promotes DNA damage-induced apoptosis and sensitizes the response to all-trans retinoic acid (ATRA) and camptothecin (CPT). Intriguingly, the expression of GDF10 is induced by type III TGF-ß receptor (TGFBR3) through TGF-ß-SMAD2/3 signaling. Our findings suggest that TGFBR3 is an upstream activator of GDF10 expression and they share the same signaling to inhibit EMT and migration/invasion. These results support that GDF10 acts as a hinge to collaborate with TGFBR3 in the transition of EMT-MET program. Taken together, we illustrated the clinical significance and the molecular mechanisms of tumor-suppressive GDF10 in OSCC.
Assuntos
Carcinoma de Células Escamosas/patologia , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Fator 10 de Diferenciação de Crescimento/metabolismo , Neoplasias Bucais/patologia , Proteoglicanas/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Fator 10 de Diferenciação de Crescimento/genética , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Prognóstico , Proteoglicanas/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Análise de SobrevidaRESUMO
S100A9 is a calcium-binding protein with two EF-hands and frequently deregulated in several cancer types, however, with no clear role in oral cancer. In this report, the expression of S100A9 in cancer and adjacent tissues from 79 early-stage oral cancer patients was detected by immunohistochemical staining. Although S100A9 protein was present in both tumor and stromal cells, only the early-stage oral cancer patients with high stromal expression had reduced recurrence-free survival. High stromal S100A9 expression was also significantly associated with non-well differentiation and recurrence. In addition to increasing cell migration and invasion, ectopic S100A9 expression in tumor cells promoted xenograft tumorigenesis as well as the dominant expression of myeloid cell markers and pro-inflammatory IL-6. The expression of S100A9 in one stromal component, monocytes, stimulated the aggressiveness of co-cultured oral cancer cells. We also detected the elevation of serum S100A9 levels in early-stage oral cancer patients of a separate cohort of 73 oral cancer patients. The release of S100A9 protein into extracellular milieu enhanced tumor cell invasion, transendothelial monocyte migration and angiogenic activity. S100A9-mediated release of IL-6 requires the crosstalk of tumor cells with monocytes through the activation of NF-κB and STAT-3. Early-stage oral cancer patients with both high S100A9 expression and high CD68+ immune infiltrates in stroma had shortest recurrence-free survival, suggesting the use of both S100A9 and CD68 as poor prognostic markers for oral cancer. Together, both intracellular and extracellular S100A9 exerts a tumor-promoting action through the activation of oral cancer cells and their associated stroma in oral carcinogenesis.
Assuntos
Biomarcadores Tumorais/biossíntese , Calgranulina B/biossíntese , Interleucina-6/biossíntese , Macrófagos/metabolismo , Neoplasias Bucais/metabolismo , Neovascularização Patológica/metabolismo , Adulto , Idoso , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Biomarcadores Tumorais/genética , Calgranulina B/genética , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Macrófagos/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/patologia , Neoplasias Bucais/irrigação sanguínea , Neoplasias Bucais/patologia , NF-kappa B/metabolismo , Invasividade Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Neovascularização Patológica/genética , Neovascularização Patológica/patologiaRESUMO
BACKGROUND: Early relapse in colorectal cancer (CRC) patients is attributed mainly to the higher malignant entity (such as an unfavorable genotype, deeper tumor invasion, lymph node metastasis and advance cancer stage) and poor response to chemotherapy. Several investigations have demonstrated that genetic polymorphisms in drug-targeted genes, metabolizing enzymes, and DNA-repairing enzymes are all strongly correlated with inter-individual differences in the efficacy and toxicity of many treatment regimens. This preliminary study attempts to identify the correlation between genetic polymorphisms and clinicopathological features of CRC, and evaluates the relationship between genetic polymorphisms and chemotherapeutic susceptibility of Taiwanese CRC patients. To our knowledge, this study discusses, for the first time, early cancer relapse and its indication by multiple genes. METHODS: Six gene polymorphisms functional in drug-metabolism - GSTP1 Ile105Val, ABCB1 Ile1145Ile, MTHFR Ala222Val, TYMS double (2R) or triple (3R) tandem repeat - and DNA-repair genes - ERCC2 Lys751Gln and XRCC1 Arg399Gln - were assessed in 201 CRC patients using a polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) technique and DNA sequencing. Patients were diagnosed as either high-risk stage II (T2 and 3 N0 M0) or III (any T N1 and 2 M0) and were administered adjuvant chemotherapy regimens that included 5-fluorouracil (5FU) and leucovorin (LV). The correlations between genetic polymorphisms and patient clinicopathological features and relapses were investigated. RESULTS: In this study, the distributions of GSTP1 (P = 0.003), ABCB1 (P = 0.001), TYMS (P < 0.0001), ERCC2 (P < 0.0001) and XRCC1 (P = 0.006) genotypes in the Asian population, with the exception of MTHFR (P = 0.081), differed significantly from their distributions in a Caucasian population. However, the unfavorable genotype ERCC2 2251A>C (P = 0.006), tumor invasion depth (P = 0.025), lymph node metastasis (P = 0.011) and cancer stage (P = 0.008) were significantly correlated with early relapse. Patients carrying the ERCC2 2251AC or2251CC genotypes had a significantly increased risk of early relapse (OR = 3.294, 95% CI, 1.272-8.532). CONCLUSION: We suggest that ERCC2 2251A>C alleles may be genetic predictors of early CRC relapse.
Assuntos
Povo Asiático/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Polimorfismo Genético , Proteína Grupo D do Xeroderma Pigmentoso/genética , Adulto , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Colectomia , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/terapia , Feminino , Fluoruracila/uso terapêutico , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Estudos Prospectivos , TaiwanRESUMO
BACKGROUND: Genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and other drug targets have been linked to inter-individual differences in the efficacy and toxicity of many medications. In the present study, multiple chemotherapeutic agent-related genetic polymorphisms, including GSTP1, MDR1, MTHFR, and TS tandem repeats, were analyzed in breast cancer patients and studied in correlation with the clinical outcome of patients receiving FEC adjuvant chemotherapy. METHODS: The genotypes from 192 stage II and III breast cancer patients who underwent operations and received six cycles of postoperative adjuvant chemotherapy (FEC) were determined by means of PCR-RFLP. The association of each genetic polymorphism with clinicopathological data of patients and early relapse status were analyzed. RESULTS: The results showed that the genotype distribution of GSTP1 A313G, MTHFR C677T, and TS 3R3R in Taiwanese subjects differed significantly from the distribution in Caucasians. After analysis of the relationship between the genotypes and clinicopathological data of the patients, a significant correlation was observed between postoperative early relapse in patients with genetic polymorphisms of both MDR1 3435CC and MTHFR 677CC (crude OR: 2.609, P = .013) and patients with additional GSTP1 313AG genetic polymorphism (crude OR: 2.833, P = .017). CONCLUSIONS: The results of the present study highly suggest that GSTP1, MDR1, and MTHFR genotypes could be prognostic factors for Taiwanese patients with breast cancer.