PDF(Pubmed)
Abstract：
Genome instability is a hallmark of cancer crucial for tumor heterogeneity and is often a result of defects in cell division and DNA damage repair. Tumors tolerate genomic instability, but the accumulation of genetic aberrations is regulated to avoid catastrophic chromosomal alterations and cell death. In ovarian cancer tumors, claudin-4 is frequently upregulated and closely associated with genome instability and worse patient outcomes. However, its biological association with regulating genomic instability is poorly understood. Here, we used CRISPR interference and a claudin mimic peptide to modulate the claudin-4 expression and its function in vitro and in vivo. We found that claudin-4 promotes a tolerance mechanism for genomic instability through micronuclei generation in tumor cells. Disruption of claudin-4 increased autophagy and was associated with the engulfment of cytoplasm-localized DNA. Mechanistically, we observed that claudin-4 establishes a biological axis with the amino acid transporters SLC1A5 and LAT1, which regulate autophagy upstream of mTOR. Furthermore, the claudin-4/SLC1A5/LAT1 axis was linked to the transport of amino acids across the plasma membrane as one of the potential cellular processes that significantly decreased survival in ovarian cancer patients. Together, our results show that the upregulation of claudin-4 contributes to increasing the threshold of tolerance for genomic instability in ovarian tumor cells by limiting its accumulation through autophagy.
UNASSIGNED: Autophagy regulation via claudin-4/SLC1A5/LAT1 has the potential to be a targetable mechanism to interfere with genomic instability in ovarian tumor cells.
UNASSIGNED: Autophagy regulation via claudin-4/SLC1A5/LAT1 has the potential to be a targetable mechanism to interfere with genomic instability in ovarian tumor cells.
摘要：
基因组不稳定性是对肿瘤异质性至关重要的癌症的标志，并且通常是细胞分裂和DNA损伤修复缺陷的结果。肿瘤耐受基因组不稳定性，但是遗传畸变的积累受到调节，以避免灾难性的染色体改变和细胞死亡。在卵巢癌肿瘤中，claudin-4经常上调,并与基因组不稳定和患者预后较差密切相关.然而,它与调节基因组不稳定性的生物学关联知之甚少。这里,我们使用CRISPR干扰和claudin模拟肽(CMP)在体外和体内调节claudin-4的表达及其功能。我们发现claudin-4通过在肿瘤细胞中产生微核来促进对基因组不稳定性的耐受机制。claudin-4的破坏增加了自噬，并与细胞质定位的DNA的吞噬有关。机械上,我们观察到claudin-4与调节mTOR上游自噬的氨基酸转运蛋白SLC1A5和LAT1建立了生物学轴.此外，claudin-4/SLC1A5/LAT1轴与氨基酸跨质膜转运相关,这是显著降低卵巢癌患者生存率的潜在细胞过程之一.一起,我们的研究结果表明，claudin-4的上调有助于通过自噬限制其积累，从而提高卵巢肿瘤细胞对基因组不稳定性的耐受阈值。
