RESUMO
Although platinum-based chemotherapy is the frontline regimen for colorectal cancer (CRC), drug resistance remains a major challenge affecting its therapeutic efficiency. However, there is limited research on the correlation between chemotherapy resistance and lipid metabolism, including PIK3CA mutant tumors. In this present study, we found that PIK3CA-E545K mutation attenuated cell apoptosis and increased the cell viability of CRC with L-OHP treatment in vitro and in vivo. Mechanistically, PIK3CA-E545K mutation promoted the nuclear accumulation of SREBP1, which promoted the transcription of Apolipoprotein A5 (APOA5). APOA5 activated the PPARγ signaling pathway to alleviate reactive oxygen species (ROS) production following L-OHP treatment, which contributed to cell survival of CRC cells. Moreover, APOA5 overexpression enhanced the stemness-related traits of CRC cells. Increased APOA5 expression was associated with PIK3CA mutation in tumor specimens and poor response to first-line chemotherapy, which was an independent detrimental factor for chemotherapy sensitivity in CRC patients. Taken together, this study indicated that PIK3CA-E545K mutation promoted L-OHP resistance by upregulating APOA5 transcription in CRC, which could be a potent target for improving L-OHP chemotherapeutic efficiency. Our study shed light to improve chemotherapy sensitivity through nutrient management in CRC.
Assuntos
Apolipoproteína A-V , Classe I de Fosfatidilinositol 3-Quinases , Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Mutação , Oxaliplatina , Espécies Reativas de Oxigênio , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Apolipoproteína A-V/genética , Apolipoproteína A-V/metabolismo , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Animais , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Camundongos , Masculino , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Reduction malarplasty presents challenges in terms of postoperative complications, particularly limited mouth opening. Excessive inward displacement of the zygomatic complex can impinge on the coronoid process resulting in restricted mouth opening. This study aimed to assess the spatial relationship between the coronoid process and the zygomatic complex after reduction malarplasty. METHODS: A retrospective study was conducted, including consecutive patients underwent reduction malarplasty. Radiological measurements were performed before surgery and during the final follow-up, including the coronoid-condylar index, distance between the coronoid process and zygomatic complex, and thickness and density of the temporal and masseter muscles. Clinical and radiographic data were recorded and analyzed. RESULTS: A total of 159 female patients were included with an average age of 28.1 years and a mean follow-up of 6.7 months. The mean coronoid-condylar index was 1:1.4, ranging from 1:0.6 to 1:2.6. Following surgery, the distances between the coronoid process and the anterior zygoma decreased by approximately 1 mm. Additionally, the postoperative distance between the highest point of the coronoid process and the zygomatic arch decreased by around 4 mm horizontally and changed approximately 1 mm vertically. No significant changes were observed in the thickness and density of the temporal and masseter muscles after surgery. CONCLUSIONS: Reduction malarplasty led to a slight decrease in the distance between the coronoid process and the zygoma. The operation generally resulted in proximity between the highest point of the coronoid process and the zygomatic arch. However, we believe that common reduction malarplasty rarely leads to osseous impingement. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.