Background

The aberrant expression of serine/threonine kinase 33 (STK33) has been implicated in cancers. However, its clinical significance and biological functions in diffuse large B cell lymphoma (DLBCL) remain largely unknown. In the present investigation, we delineated the expression of STK33 in DLBCL and its function in cisplatin resistance.

Methods

First, genes associated with drug resistance as well as occurrence in DLBCL were analyzed by bioinformatics, followed by correlation analysis between STK33 expression and clinical baseline information of patients with DLBCL. Further, cisplatin-resistant DLBCL cell lines were constructed, and changes in cell sensitivity to cisplatin treatment were examined after interfering the expression of STK33 in parental cells as well as in drug-resistant cells, respectively. Subsequently, the downstream signaling pathways of STK33 were analyzed. Finally, the upstream regulatory mechanism of STK33 was predicted by bioinformatics as well as experimentally validated.

Results

STK33 was overexpressed in the patients with DLBCL as well as in cisplatin-resistant DLBCL cells, and knockdown of STK33 significantly promoted sensitivity of resistant cells to cisplatin. Moreover, our further analysis revealed that STK33 promoted cisplatin resistance in DLBCL by activating the Hedgehog signaling pathway. We found in subsequent experiments that nuclear transcription factor Y subunit beta (NFYB) can bind to the STK33 promoter and thus promote STK33 expression.

Conclusions

The transcription factor NFYB expedites the transcription of SYK33 by binding to the STK33 promoter, thereby activating the Hedgehog signaling pathway in DLBCL cells, which in turn promotes the resistance of DLBCL cells to cisplatin.

中文翻译：

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NFYB 增强 STK33 活化以促进弥漫性大 B 细胞淋巴瘤中的顺铂耐药

背景

丝氨酸/苏氨酸激酶 33 (STK33) 的异常表达与癌症有关。然而，其在弥漫性大 B 细胞淋巴瘤 (DLBCL) 中的临床意义和生物学功能仍然很大程度上未知。在本研究中，我们描述了 STK33 在 DLBCL 中的表达及其在顺铂耐药中的作用。

方法

首先，通过生物信息学分析与耐药性以及DLBCL发生相关的基因，然后分析STK33表达与DLBCL患者临床基线信息的相关性。此外，构建了顺铂耐药的DLBCL细胞系，分别在干扰亲代细胞和耐药细胞中STK33的表达后，检测了细胞对顺铂处理的敏感性变化。随后，分析了STK33的下游信号通路。最后，通过生物信息学预测了STK33的上游调控机制，并进行了实验验证。

结果

STK33 在 DLBCL 患者以及顺铂耐药的 DLBCL 细胞中过表达，STK33 的敲低显着提高了耐药细胞对顺铂的敏感性。此外，我们的进一步分析表明，STK33 通过激活 Hedgehog 信号通路促进 DLBCL 中的顺铂耐药。我们在随后的实验中发现，核转录因子 Y 亚基β (NFYB) 可以与 STK33 启动子结合，从而促进 STK33 的表达。

结论

转录因子NFYB通过与STK33启动子结合来加速SYK33的转录，从而激活DLBCL细胞中的Hedgehog信号通路，进而促进DLBCL细胞对顺铂的耐药性。