目前肝癌是癌症造成死亡人數第四名，研究肝癌形成和發展的分子機制，將對癌症治療和預防產生益處。在我們先前的研究表明，USP24通過調節細胞週期進展、凋亡和轉移參與肺癌的進展，並且USP24可以通過誘導基因組不穩定性和增加ABC轉運蛋白來誘導藥物抗性。此外我們還開發了一種新型的USP24抑制劑USP24-i，以抵抗肺癌化療中獲得的藥物抗性。在這項研究中，我們將探討USP24-i對肝癌的影響。首先，我們研究了肝癌細胞系和來自THE HUMAN PROTEIN ATLAS的肝癌標本中USP24的水平。數據表明與正常組織相比，肝癌細胞和患者中USP24的表達水平高，暗示USP24可能參與了肝癌的進展。其次，我們在肝細胞系Huh7和HepG2中靜默了USP24，以研究USP24在肝癌進展中的作用。結果顯示，靜默USP24顯著抑制了細胞生長和癌細胞的遷移。接著，通過USP24-i靶向USP24，研究USP24-i對抑制癌細胞生長和癌細胞轉移的影響。有趣的是，USP24-i處理通過自噬依賴的凋亡誘導細胞死亡。此外我們的研究表明USP24與肝癌中的脂質代謝之間的關聯，將肝癌細胞與致癌的游離脂肪酸處理後，USP24蛋白質和mRNA的表達水平增加，暗示USP24參與了脂質誘導的肝癌進展。這是首次研究USP24在肝癌進展中的作用，將為支持USP24在肝癌中的作用提供證據。

Liver cancer is the fourth-leading cause of cancer death, and the incidence of liver cancer is the seventh-leading cause worldwide. Understanding the molecular mechanisms of how to develop liver cancer formation and malignancy and thereby develops useful anti-cancer strategies will be beneficial for cancer therapy and prevention. Our previous studies show that USP24 is involved in lung cancer progression through modulating cell cycle progression, apoptosis, and metastasis. Recently, we also found that USP24 can induce drug resistance through inducing genomic instability and increasing ABC transporters. Furthermore, we also developed a novel specific USP24 inhibitor USP24-i to block the drug resistance acquired in chemotherapy in lung cancer. In this study, we will address the effect of USP24-i on liver cancer. At first, we studied the level of USP24 in liver cancer cell lines and liver cancer specimen from THE HUMAN PROTEIN ATLAS. The data indicated that USP24 is highly expressed in liver cancer cells and patients compared to the normal tissue, indicating that USP24 might be involved in liver cancer progression. Second, USP24 was knockdown in liver cell lines, Huh7 and HepG2, to study the role of USP24 on liver cancer progression. The results indicated that knockdown of USP24 significantly inhibited cell growth and cancer cell migration. Next, targeting USP24 by USP24-i to study the effect of USP24-i on inhibiting cancer cell growth and cancer cell metastasis. Interestingly, USP24-i treatment significantly induce cell death though autophagy-dependent apoptosis. Furthermore, our study unveiled a connection between USP24 and lipid metabolism in liver cancer. Treatment of Huh7 cells with pro-oncogenic FFAs led to increased USP24 protein and mRNA expression levels, suggesting USP24's involvement in lipid-induced progression of liver cancer. In summary, our findings illuminate the multifaceted role of USP24 in liver cancer, impacting cell proliferation, migration, apoptosis, and autophagy. The synthesized USP24 inhibitor holds promise as a potential therapeutic avenue, particularly for cells with elevated USP24 expression, and the intricate relationship between USP24 and lipid metabolism during the progression of liver cancer.

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