Aberrant PI3Kδ splice isoform as a potential biomarker and novel therapeutic target for endocrine cancers.
Aberrant PI3Kδ splice isoform as a potential biomarker and novel therapeutic target for endocrine cancers.
复制标题
DOI：
10.3389/fendo.2023.1190479
复制
发表时间：
2023
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
--
作者：
PI3K/AKT信号通路在多种肿瘤中表达上调。在I类PI3K(PI3Kδ/β/δ异构体)中，PI3Kδ与血液病和实体瘤有关。选择性剪接是获得真核细胞蛋白质组多样性的转录后过程。越来越多的证据表明，异常的信使核糖核酸剪接参与了癌症的发生和发展。我们先前的研究表明，PIK3CD-S是一种癌基因剪接变异体，可促进前列腺癌(Pca)的肿瘤侵袭性和耐药性。为了进一步评估利用PI3Kδ-S(由PIK3CD-S编码)作为肿瘤生物标志物和/或药物靶点的潜力，我们对一系列来自内分泌/实体肿瘤的患者样本和细胞系进行了全面的分析。免疫组化、免疫荧光、免疫印迹和RT-PCR法检测结果表明，PI3Kδ亚型在内分泌/实体瘤患者标本和细胞系中高度表达。在一组内分泌/实体瘤细胞中鉴定了PIK3CD-S/PIK3CD-L的差异表达谱。PIK3CD-L或PIK3CD-S的siRNA抑制PCa、乳腺癌细胞、结肠癌和肺癌细胞株的AKT/mTOR信号转导。此外，pTensiRNA敲除后，癌细胞中PI3Kδ水平升高，AKT/mTOR信号转导激活，而PTEN过表达则降低PI3Kδ水平，抑制AKT/mTOR信号转导。有趣的是，PI3KPTEN-S的水平在siRNA下调或过度表达δ的情况下保持不变。综上所述，这些结果提示PTEN对PI3Kδ-L及其下游的AKT/mTOR信号转导具有负性调节作用，而PI3Kδ-S促进AKT/mTOR信号转导而不受PTEN的调控。最后，应用PI3Kδ抑制剂依得利西布和SRPK1/2抑制剂SRPIN340来评价它们对表达PI3Kδ的内分泌/实体瘤的抑制作用。我们的结果表明，伊德利西布有效地抑制了PI3Kδ-L(而不是PI3Kδ-S)介导的AKT/mTOR信号转导。相反，SRPIN340逆转了异常的mRNA剪接，从而抑制了AKT/mTOR信号。体外功能分析进一步证明，Idelalisib和SRPIN340联合使用在抑制晚期肿瘤细胞方面具有协同药物效应(显著降低细胞存活率/肿瘤球体生长)。综上所述，我们的研究表明，利用PI3KPTEN-S(一种导致耐药且不受δ调控的癌基因异构体)作为晚期内分泌癌的预后生物标志物和药物靶点具有很大的潜力。
PI3K/AKT signaling pathway is upregulated in a broad spectrum of cancers. Among the class I PI3Ks (PI3Kδ/β/δ isoforms), PI3Kδ has been implicated in hematologic cancers and solid tumors. Alternative splicing is a post-transcriptional process for acquiring proteomic diversity in eukaryotic cells. Emerging evidence has highlighted the involvement of aberrant mRNA splicing in cancer development/progression. Our previous studies revealed that PIK3CD-S is an oncogenic splice variant that promotes tumor aggressiveness and drug resistance in prostate cancer (PCa). To further evaluate the potential of utilizing PI3Kδ-S (encoded from PIK3CD-S) as a cancer biomarker and/or drug target, comprehensive analyses were performed in a series of patient samples and cell lines derived from endocrine/solid tumors. Specifically, IHC, immunofluorescence, western blot and RT-PCR assay results have demonstrated that PI3Kδ isoforms were highly expressed in endocrine/solid tumor patient specimens and cell lines. Differential PIK3CD-S/PIK3CD-L expression profiles were identified in a panel of endocrine/solid tumor cells. SiRNA knockdown of PIK3CD-L or PIK3CD-S differentially inhibits AKT/mTOR signaling in PCa, breast, colon and lung cancer cell lines. Moreover, siRNA knockdown of PTEN increased PI3Kδ levels and activated AKT/mTOR signaling, while overexpression of PTEN reduced PI3Kδ levels and inhibited AKT/mTOR signaling in cancer cells. Intriguingly, PI3Kδ-S levels remained unchanged upon either siRNA knockdown or overexpression of PTEN. Taken together, these results suggested that PTEN negatively regulates PI3Kδ-L and its downstream AKT/mTOR signaling, while PI3Kδ-S promotes AKT/mTOR signaling without regulation by PTEN. Lastly, PI3Kδ inhibitor Idelalisib and SRPK1/2 inhibitor SRPIN340 were employed to assess their efficacies on inhibiting the PI3Kδ-expressing endocrine/solid tumors. Our results have shown that Idelalisib effectively inhibited PI3Kδ-L (but not PI3Kδ-S) mediated AKT/mTOR signaling. In contrast, SRPIN340 reversed the aberrant mRNA splicing, thereby inhibiting AKT/mTOR signaling. In-vitro functional assays have further demonstrated that a combination of Idelalisib and SRPIN340 achieved a synergistic drug effect (with drastically reduced cell viabilities/growths of tumor spheroids) in inhibiting the advanced tumor cells. In summary, our study has suggested a promising potential of utilizing PI3Kδ-S (an oncogenic isoform conferring drug resistance and exempt from PTEN regulation) as a prognostic biomarker and drug target in advanced endocrine cancers.
登录
查看更多内容
PLZF 介导 PTEN/AKT/FOXO3a 信号传导抑制前列腺肿瘤发生。
影响因子：
3.7
作者：
Cao J;Zhu S;Zhou W;Li J;Liu C;Xuan H;Yan J;Zheng L;Zhou L;Yu J;Chen G;Huang Y;Yu Z;Feng L
通讯作者：
Feng L
影响因子：
5.6
作者：
通讯作者：
--
DOI：
10.1186/s13046-019-1260-6
发表时间：
2019-06-13
影响因子：
11.3
作者：
Gao, Xue;Qin, Tao;Li, Lianhong
通讯作者：
Li, Lianhong
影响因子：
4.7
作者：
Bermúdez Brito M;Goulielmaki E;Papakonstanti EA
通讯作者：
Papakonstanti EA
PIK3CD 通过激活结直肠癌中的 AKT/GSK-3 β/β-catenin 信号传导诱导细胞生长和侵袭
影响因子：
5.7
作者：
Chen, Jing-Song;Huang, Jiong-Qiang;Zhong, Jian-Feng
通讯作者：
Zhong, Jian-Feng