Wang Zhongyong, Li Zhiyu, Xu Hui, Liao Yun, Sun Chao, Chen Yanming, Sheng Minfeng, Lan Qing, Wang Zhong
Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
Ann Transl Med. 2021 Apr;9(8):700. doi: 10.21037/atm-21-1481.
Glioma is the most common and aggressive primary brain tumor in adults. Proteasome 26S subunit, non-ATPase 12 (PSMD12), an important subunit in the 26S proteasome, is known to be involved in the growth and apoptosis of breast cancer cells. However, its exact function and underlying molecular mechanisms in glioma remain unknown.
PSMD12 expression was detected in glioma tissue specimens by immunohistochemistry (IHC) and TCGA database. Overexpression and down-regulation of PSMD12 and Nrf2 were induced in glioma cell lines, and CCK-8 and Transwell assays were used to detect cell proliferation and invasion evaluation, respectively. Xenograft model was used to observe the effect of knockdown of PSMD12 on tumor growth. Immunohistochemical assays and TCGA database were conducted to reveal the relationships between PSMD12 expression and Nrf2. Finally, Western blot and related biological function experiments were used to explore the mechanism of PSMD12 regulating the glioma progression and Nrf2.
We revealed that PSMD12 is upregulated in glioma, especially in high-grade glioma, by analyzing bioinformatics data and clinical specimens. PSMD12 upregulation was associated with poor prognosis in glioma patients. Knockdown of PSMD12 inhibited the growth of glioma cells and and decreased their invasion ability, whereas PSMD12 overexpression had the opposite effect. Mechanistic analysis revealed that PSMD12 increased the expression of nuclear factor E2-related factor 2 (Nrf2), which functions as a tumor promoter in the development of glioma. Similar to PSMD12, Nrf2, which exhibited a strong positive correlation with PSMD12, was abnormally elevated in glioma tissues and contributed to worse overall survival (OS). Nrf2 overexpression reversed the inhibitory effects induced by PSMD12 knockdown. Finally, PSMD12 enhanced the proliferation and invasion of glioma cells via Akt signaling-mediated Nrf2 expression.
These results suggest that PSMD12 is considered to be a crucial regulator of the development and progression of glioma and may serve as a potential biomarker or therapeutic target for the treatment of glioma.
胶质瘤是成人中最常见且侵袭性最强的原发性脑肿瘤。蛋白酶体26S亚基非ATP酶12（PSMD12）是26S蛋白酶体中的一个重要亚基，已知其参与乳腺癌细胞的生长和凋亡。然而，其在胶质瘤中的确切功能及潜在分子机制仍不清楚。
通过免疫组织化学（IHC）和TCGA数据库检测胶质瘤组织标本中PSMD12的表达。在胶质瘤细胞系中诱导PSMD12和Nrf2的过表达及下调，分别采用CCK - 8和Transwell实验检测细胞增殖和侵袭能力评估。利用异种移植模型观察敲低PSMD12对肿瘤生长的影响。进行免疫组织化学分析和TCGA数据库分析以揭示PSMD12表达与Nrf2之间的关系。最后，采用蛋白质印迹法和相关生物学功能实验探究PSMD12调节胶质瘤进展和Nrf2的机制。
通过分析生物信息学数据和临床标本，我们发现PSMD12在胶质瘤中上调，尤其是在高级别胶质瘤中。PSMD12上调与胶质瘤患者预后不良相关。敲低PSMD12可抑制胶质瘤细胞生长并降低其侵袭能力，而PSMD12过表达则有相反作用。机制分析表明，PSMD12增加了核因子E2相关因子2（Nrf2）的表达，Nrf2在胶质瘤发生发展中起肿瘤促进作用。与PSMD12相似，与PSMD12呈强正相关的Nrf2在胶质瘤组织中异常升高，并导致总体生存率（OS）更差。Nrf2过表达逆转了PSMD12敲低所诱导的抑制作用。最后，PSMD12通过Akt信号介导的Nrf2表达增强胶质瘤细胞的增殖和侵袭。
这些结果表明，PSMD12被认为是胶质瘤发生发展的关键调节因子，可能作为治疗胶质瘤的潜在生物标志物或治疗靶点。
