10-甲酰四氢叶酸脱氢酶异常下调通过激活 PI3K/Akt/Rb 通路促进口腔鳞状细胞癌的进展。
Abnormal downregulation of 10-formyltetrahydrofolate dehydrogenase promotes the progression of oral squamous cell carcinoma by activating PI3K/Akt/Rb pathway.
机构信息
Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China.
出版信息
Cancer Med. 2023 Mar;12(5):5781-5797. doi: 10.1002/cam4.5327. Epub 2022 Nov 6.
BACKGROUND
10-formyltetrahydrofolate dehydrogenase (ALDH1L1) is a major folate enzyme, which is usually underexpressed in malignant tumors and competes with tumors for the same folate substrate. However, the specific role and mechanisms of ALDH1L1 in oral squamous cell carcinoma (OSCC) remainsobscure.
METHODS
The expression level of ALDH1L1 in paired OSCC tissues and adjacent noncancerous tissues were detected by quantitative realtime PCR, Western blot and immunohistochemistry. The relationship between ALDH1L1 expression and clinical characteristics was analyzed. Besides, CCK8, EdU staining, colony formation, wound healing, transwell invasion, apoptosis, cell cycle assays and nude mice tumor bearing experiments were employed to assess the role of ALDH1L1 in OSCC. To explore the underlying mechanisms of these effects, cell cycle-related markers were examined.
RESULTS
In this study, we revealed that ALDH1L1 expression was significantly reduced in OSCC, and its downregulation was associated with the malignancy of the tumor and poor prognosis of patients. In vivo and in vitro experiments, downregulation of ALDH1L1 in OSCC significantly inhibited the occurrence of NADP -dependent catalytic reactions and facilitated tumor cell growth, migration, invasion, survival, cell cycle progression, and xenograft tumor growth. On the contrary, re-expression of ALDH1L1 plays a similar role to anti-folate therapy, promoting NADPH production and suppressing the progression of OSCC. Furthermore, ALDH1L1 overexpressing obviously inhibited the expression of PI3K, p-Akt, CDK2, CDK6, Cyclin D1, Cyclin D3, and Rb in OSCC cells, and promoted the expression of p27. LY294002 and 740 Y-P were used to confirm the inhibitory effects of ALDH1L1 on OSCC progression through PI3K/Akt/Rb pathway.
CONCLUSION
Our findings highlight the clinical value of ALDH1L1 as a prognostic marker and the potential of a new target for anti-folate therapy.
背景
10-甲酰四氢叶酸脱氢酶（ALDH1L1）是一种主要的叶酸酶，通常在恶性肿瘤中表达下调，与肿瘤竞争相同的叶酸底物。然而，ALDH1L1 在口腔鳞状细胞癌（OSCC）中的具体作用和机制尚不清楚。
方法
通过实时定量 PCR、Western blot 和免疫组织化学检测配对的 OSCC 组织和相邻非癌组织中 ALDH1L1 的表达水平。分析 ALDH1L1 表达与临床特征的关系。此外，还进行了 CCK8、EdU 染色、集落形成、划痕愈合、Transwell 侵袭、细胞凋亡、细胞周期检测和裸鼠荷瘤实验，以评估 ALDH1L1 在 OSCC 中的作用。为了探讨这些影响的潜在机制，检测了与细胞周期相关的标志物。
结果
在本研究中，我们揭示 ALDH1L1 的表达在 OSCC 中显著降低，其下调与肿瘤的恶性程度和患者的预后不良有关。在体内和体外实验中，下调 OSCC 中的 ALDH1L1 显著抑制 NADP 依赖性催化反应的发生，并促进肿瘤细胞的生长、迁移、侵袭、存活、细胞周期进程和异种移植肿瘤的生长。相反，ALDH1L1 的重新表达发挥了类似抗叶酸治疗的作用，促进 NADPH 的产生并抑制 OSCC 的进展。此外，ALDH1L1 过表达明显抑制 OSCC 细胞中 PI3K、p-Akt、CDK2、CDK6、Cyclin D1、Cyclin D3 和 Rb 的表达，并促进 p27 的表达。使用 LY294002 和 740 Y-P 证实了 ALDH1L1 通过 PI3K/Akt/Rb 通路对 OSCC 进展的抑制作用。
结论
我们的研究结果强调了 ALDH1L1 作为预后标志物的临床价值，以及作为抗叶酸治疗新靶点的潜力。
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