Phosphodiesterase 12 facilitates the growth and metastatic capabilities of gastric cancer cells by activating the TCAF2/JAK2/STAT3 axis

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-07-06 DOI:10.1016/j.bbadis.2025.167973

Yi-Jin Liu, Huan-Xi Song, Jia-Hui Li, Xin-Ya Wang, Xiao-Fei Nie, Li-Na Zhang

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引用次数: 0

Abstract

Phosphodiesterase 12 (PDE12), also known as 2′-PDE, is a key molecule in the 2-5A antiviral system and a member of the endonuclease-exonuclease-phosphatase (EEP) superfamily of deadenylases. Current research on PDE12 mainly focuses on mitochondrial mRNA degradation, mitochondrial protein translation, and the related human diseases caused by mitochondrial oxidative phosphorylation disruption. However, the biological role and molecular mechanisms of PDE12 in human cancers remains unclear. In the present study, we found that PDE12 was highly expressed in gastric cancer tissues and gastric cancer cell lines. Gain- and loss-of-function experiments confirmed that PDE12 promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of gastric cancer cells. PDE12 also promoted G1-S phase transition of gastric cancer cells by regulating the expression of G1 phase-specific Cyclin D1/CDK4 and Cyclin E/CDK2. Our further studies indicated that PDE12 positively regulated the expression of TRPM8 channel-associated factor 2 (TCAF2), which functioned as an oncogene in gastric cancer progression. TCAF2 knockdown significantly suppressed gastric cancer cell proliferation, migration and invasion, and reversed the promoting effect of PDE12 overexpression on gastric cancer cell growth and metastasis. Furthermore, our findings revealed a novel mechanism by which PDE12/TCAF2 axis promoted gastric cancer progression by activating the JAK2/STAT3 signaling pathway. Taken together, our data strongly indicate that PDE12 exerts an oncogenic function in gastric cancer progression at least partly via activating the TCAF2/JAK2/STAT3 signaling axis. These findings provide new insights into the tumorigenesis and metastasis of gastric cancer, and suggest that PDE12 may serve as a novel therapeutic target for gastric cancer.

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磷酸二酯酶12通过激活TCAF2/JAK2/STAT3轴促进胃癌细胞的生长和转移能力

磷酸二酯酶12 (PDE12)，又称2′-PDE，是2- 5a抗病毒系统的关键分子，也是内切酶-外切酶-磷酸酶（EEP）死烯酶超家族的成员。目前对PDE12的研究主要集中在线粒体mRNA降解、线粒体蛋白翻译以及线粒体氧化磷酸化破坏引起的相关人类疾病。然而，PDE12在人类癌症中的生物学作用和分子机制尚不清楚。在本研究中，我们发现PDE12在胃癌组织和胃癌细胞系中高表达。功能获得和功能丧失实验证实PDE12促进了胃癌细胞的增殖、迁移、侵袭和上皮-间质转化（EMT）。PDE12还通过调节G1期特异性Cyclin D1/CDK4和Cyclin E/CDK2的表达，促进胃癌细胞G1- s期转变。我们进一步的研究表明PDE12正调控TRPM8通道相关因子2 （TCAF2）的表达，TCAF2在胃癌进展中起致癌基因的作用。TCAF2敲低可显著抑制胃癌细胞的增殖、迁移和侵袭，逆转PDE12过表达对胃癌细胞生长和转移的促进作用。此外，我们的研究结果揭示了PDE12/TCAF2轴通过激活JAK2/STAT3信号通路促进胃癌进展的新机制。综上所述，我们的数据强烈表明PDE12至少部分通过激活TCAF2/JAK2/STAT3信号轴在胃癌进展中发挥致癌功能。这些发现为胃癌的发生和转移提供了新的认识，并提示PDE12可能成为胃癌新的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.