Abnormal downregulation of 10-formyltetrahydrofolate dehydrogenase promotes the progression of oral squamous cell carcinoma by activating PI3K/Akt/Rb pathway.
Abnormal downregulation of 10-formyltetrahydrofolate dehydrogenase promotes the progression of oral squamous cell carcinoma by activating PI3K/Akt/Rb pathway.
复制标题
10种甲基四氢叶酸脱氢酶的异常下调通过激活PI3K/AKT/RB途径来促进口服鳞状细胞癌的进展。
作者：
10-甲酰四氢叶酸脱氢酶（ALDH 1 L1）是一种主要的叶酸酶，通常在恶性肿瘤中表达不足，并与肿瘤竞争相同的叶酸底物。然而，ALDH 1 L1在口腔鳞状细胞癌（oral squamous cell carcinoma，OSCC）中的具体作用和机制尚不清楚。采用实时荧光定量PCR、Western blot和免疫组化方法检测ALDH 1 L1在配对口腔鳞癌组织及癌旁组织中的表达水平。分析ALDH 1 L1表达与临床特征的关系。此外，还采用CCK 8、EdU染色、集落形成、伤口愈合、transwell侵袭、细胞凋亡、细胞周期分析和裸鼠移植瘤实验等方法研究ALDH 1 L1在口腔鳞癌中的作用。为了探索这些作用的潜在机制，检查了细胞周期相关标志物。在这项研究中，我们发现ALDH 1 L1在口腔鳞癌中的表达显著降低，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，ALDH 1 L1在OSCC中的下调显著抑制NADP+依赖性催化反应的发生，并促进肿瘤细胞生长、迁移、侵袭、存活、细胞周期进展和异种移植肿瘤生长。相反，ALDH 1 L1的再表达与抗叶酸治疗起着类似的作用，促进NADPH的产生并抑制OSCC的进展。ALDH 1 L1过表达明显抑制PI 3 K、p-Akt、CDK 2、CDK 6、Cyclin D1、Cyclin D3和Rb的表达，促进p27的表达。使用LY 294002和740 Y-P来证实ALDH 1 L1通过PI 3 K/Akt/Rb通路对OSCC进展的抑制作用。我们的研究结果强调了ALDH 1 L1作为预后标志物的临床价值，以及抗叶酸治疗新靶点的潜力。抗叶酸治疗在多种实体恶性肿瘤的治疗中取得了显著的效果。在本研究中，我们发现叶酸酶ALDH 1 L1通过灭活PI 3 K/Akt/Rb信号通路来抑制OSCC的进展。这为抗叶酸治疗提供了潜在的新靶点。
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. 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. 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. Our findings highlight the clinical value of ALDH1L1 as a prognostic marker and the potential of a new target for anti‐folate therapy. Anti‐folate therapy has achieved remarkable results in the treatment of a variety of solid malignancies. In the present study, we revealed that the folate enzyme ALDH1L1 inhibits OSCC progression by deactivating the PI3K/Akt/Rb signaling pathway. This provides a potential new target for anti‐folate therapy.
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影响因子：
5.1
作者：
Krupenko, Natalia I.;Holmes, Roger S.;Tsybovsky, Yaroslav;Krupenko, Sergey A.
通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
5.1
作者：
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通讯作者：
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影响因子：
3.7
作者：
Khan, Qasim A.;Pediaditakis, Peter;Krupenko, Sergey A.
通讯作者：
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影响因子：
8
作者：
Oleinik, N. V.;Krupenko, N. I.;Krupenko, S. A.
通讯作者：
Krupenko, S. A.