肺癌為致死率極高的癌症之一，在發展過程中或治療後，腫瘤異質性及併發症常致使較差預後。盡管如此，現今相關探討仍多侷限在體外試驗；為此，我們建構出體內肺癌模式並分別探討p53及USP24在肺癌的gefitinib抗藥性以及併發心血管疾病的角色。使用的小鼠基因背景包含可誘導表現突變EGFR (EGFRL858R)、部分p53缺失 (p53+/-) 以及酵素性位點缺失的USP24 (USP24C1695A/C1695A)；由此，我們發現了p53對gefitinib抗藥性調控的可能方式以及USP24促使心血管疾病的角色。在對gefitinib具抗藥性的情況下，p53+/-小鼠減少了鄰近p53的基因突變以及截然不同的基因表現樣貌，並可能以此促使gefitinib抗藥性產生。另外，在誘導出肺部腫瘤的情況下，USP24C1695A/ C1695A小鼠的心血管疾病症狀較為輕微，且心臟纖維化相關基因之表現也較低下。我們更進一步在以cisplatin或TGF-β誘導纖維化後，處理以USP24專一性的抑制劑 - USP24-i-101；而後；我們發現大鼠心臟肌肉細胞株H9c2的纖維化相關基因 - FN1、FSP1、CCN2、POSTN、COL1A1以及COL3A1 均受USP24-i-101抑制。此外，在肺癌細胞株A549處理以USP24-i-101或降低USP24表現亦能以釋放至培養基的物質間接抑制H9c2在纖維化基因的表現。根據USP24對心臟纖維化的直接或間接促進，以USP24為標的或能藉由抑制心臟纖維化以維持心臟功能，進而減少肺癌病人在肺癌進程中或治療後的心因性死亡。

Lung cancer has been one of the leading causes of death. Tumor heterogeneity and simultaneous complications develop during the progression of cancer and often result in poor survival rates post treatments. However, most studies related to heterogeneous tumors were conducted in vitro. We had established an in vivo lung cancer model to demonstrate the role of p53 and USP24 in gefitinib resistance and simultaneous cardiovascular disease (CVD), respectively. With the mice expressing inducible mutated EGFR (EGFRL858R), partial loss of p53 (p53+/-), and enzymatically abolished USP24 (USP24C1695A/ C1695A), we found the potential approaches of p53 modulating gefitinib resistance and the assisting role of USP24 in CVD. Under the gefitinib-resistant conditions, p53+/- mice displayed alleviated mutation frequency on the loci close to Tp53 and a distinct gene expression profile, resulting in enhanced gefitinib resistance. Under lung tumor-bearing conditions, USP24C1695A/ C1695A mice developed less severe CVD symptoms and less expression of cardiac fibrosis-related genes. Furthermore, targeting USP24 during the treatment of cisplatin or TGF-β with a specific inhibitor, USP24-i-101, decreased cardiac fibrosis-related genes, FN1, FSP1, CCN2, POSTN, COL1A1, and COL3A1, in a rat cardiomyocyte cell line, H9c2. Additionally, USP24-i-101 treatment or USP24 knockdown indirectly decreased fibrosis-related gene expression in H9c2 via the conditional medium collected from a lung cancer cell line, A549. According to the positive regulation of USP24 in fibrosis, targeting USP24 may maintain cardiac function by inhibiting cardiac fibrosis, which may reduce the CVD-leading death of lung cancer patients during cancer progression or post therapies.

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