在高级浆液性卵巢癌中,BRD4长(BRD4-L)和短(BRD4-S)的表达增加会促进化疗抵抗性的发展。
Increased expression of BRD4 isoforms long (BRD4-L) and short (BRD4-S) promotes chemotherapy resistance in high-grade serous ovarian carcinoma.
发表日期:2023
作者:
Ana Luiza Drumond-Bock, Luyao Wang, Lin Wang, Magdalena Cybula, Maria Rostworowska, Michael Kinter, Magdalena Bieniasz
来源:
Genes & Diseases
摘要:
卵巢癌的化学耐药性是一个令人困惑的问题,迫切需要理解癌细胞生存DNA损伤和逃避细胞死亡的策略。扩大了解导致化学耐药性的机制,并开发针对化学耐药性肿瘤的替代疗法的努力至关重要。BRD4的扩增通常与化学耐药性的卵巢癌相关,但对于在这种恶性肿瘤中BRD4亚型过表达的生物效果知之甚少。 在这里,我们描述了BRD4-L和BRD4-S在卵巢癌中过表达的后果,为BRD4亚型的复杂调控提供了一线线索。 我们证明了BRD4-L转录本表达是生成BRD4-L和BRD4-S两个亚型所必需的。我们显示了BRD4-S的mRNA表达与BRD4-S蛋白水平呈正相关,而BRD4-L亚型则显示了mRNA和蛋白水平之间的负相关。此外,我们证明了BRD4亚型的过表达与卵巢癌的化学耐药性有关。
Chemoresistance in ovarian carcinoma is a puzzling issue that urges understanding of strategies used by cancer cells to survive DNA damage and to escape cell death. Expanding efforts to understand mechanisms driving chemoresistance and to develop alternative therapies targeting chemoresistant tumors are critical. Amplification of BRD4 is frequently associated with chemoresistant ovarian carcinoma, but little is known about the biological effects of the overexpression of BRD4 isoforms in this malignancy. Here, we described the consequences of BRD4-L and BRD4-S overexpression in ovarian carcinoma shedding a light on a complex regulation of BRD4 isoforms. We demonstrated that the BRD4-L transcript expression is required to generate both isoforms, BRD4-L and BRD4-S. We showed that the BRD4-S mRNA expression positively correlated with BRD4-S protein levels, while BRD4-L isoform showed negative correlation between mRNA and protein levels. Moreover, we demonstrated that an overexpression of BRD4 isoforms is associated with chemoresistance in ovarian cancer.