PDCD10 promotes the tumor-supporting functions of TGF-β in pancreatic cancer.

IF 6.7 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Clinical science Pub Date : 2024-09-18 DOI:10.1042/CS20240450
Qianwen Zhou, Katja Breitkopf-Heinlein, Haristi Gaitantzi, Emrullah Birgin, Christoph Reissfelder, Nuh N Rahbari
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Abstract

The progression of pancreatic ductal adenocarcinoma (PDAC) is significantly affected by transforming growth factor (TGF)-β but targeting TGF-β can also compromize physiological effects in patients. Our study examined the functions of the ubiquitously expressed protein, PDCD10, as a modulator of TGF-β signaling in PDAC. Using in silico analyses we found that in patient samples, PDCD10 is significantly higher expressed in PDAC tumor tissue compared with normal pancreas and it is highly correlated with reduced survival. We created stable KO's of PDCD10 in two PDAC lines, PaTu 8902 (SMAD4 +/+) and PaTu 8988t (SMAD4 -/-), and found that KO lines are more sensitive to 5-FU and Gemcitabine treatment than their wild-type counterparts. Performing viability and wound closure assays we further found that PDCD10 promotes cell survival and proliferation by enhancing specifically the mitogenic functions of TGF-β. The molecular mechanism underlying this effect was further investigated using Western blots and with primary organoid lines derived from patient PDAC tissue samples. The data imply that PDCD10 mediates an increase in p-ERK through a non-SMAD4 pathway, leading to EMT promotion. Furthermore, PDCD10 facilitates deactivation of RB via a SMAD4-dependent pathway, thereby counter-acting the anti-proliferative actions of TGF-β. By performing proximity ligation assays (PLA) we found that PDCD10 associates with the kinase MST4, translocates it intracellularly and thereby facilitates phosphorylations of RB and ERK1/2. Our study indicates that PDCD10 promotes the proliferative function and EMT induction of TGF-β in pancreatic cancer cells. Therefore, targeting PDCD10 in PDAC patients could represent a promising new strategy to optimize TGF-β targeted therapies.

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PDCD10 在胰腺癌中促进 TGF-β 的肿瘤支持功能。
胰腺导管腺癌(PDAC)的进展受到TGF-β的显著影响,但靶向TGF-β也会损害患者的生理效应。我们的研究考察了普遍表达的蛋白质PDCD10作为TGF-β信号转导调节剂的功能。我们利用硅学分析发现,在患者样本中,PDCD10 在 PDAC 肿瘤组织中的表达明显高于正常胰腺,而且与生存率降低高度相关。我们在两个 PDAC 株系 PaTu 8902(SMAD4 +/+)和 PaTu 8988t(SMAD4 -/-)中建立了稳定的 PDCD10 KO 株系,并发现 KO 株系比野生型株系对 5-FU 和吉西他滨治疗更敏感。在进行存活率和伤口闭合试验时,我们进一步发现 PDCD10 能通过增强 TGF-β 的有丝分裂功能促进细胞存活和增殖。我们利用 Western 印迹和从 PDAC 患者组织样本中提取的原代类器官系进一步研究了这种效应的分子机制。数据表明,PDCD10通过非SMAD4途径介导了p-ERK的增加,从而导致EMT的促进。此外,PDCD10 通过 SMAD4 依赖性途径促进 RB 失活,从而抵消了 TGF-β 的抗增殖作用。通过近距离接合试验(PLA),我们发现 PDCD10 与激酶 MST4 结合,将其转运到细胞内,从而促进 RB 和 ERK1/2 的磷酸化。我们的研究表明,PDCD10 促进了胰腺癌细胞的增殖功能和 TGF-β 的 EMT 诱导。因此,在 PDAC 患者中靶向 PDCD10 可能是优化 TGF-β 靶向疗法的一种有前途的新策略。
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来源期刊
Clinical science
Clinical science 医学-医学:研究与实验
CiteScore
11.40
自引率
0.00%
发文量
189
审稿时长
4-8 weeks
期刊介绍: Translating molecular bioscience and experimental research into medical insights, Clinical Science offers multi-disciplinary coverage and clinical perspectives to advance human health. Its international Editorial Board is charged with selecting peer-reviewed original papers of the highest scientific merit covering the broad spectrum of biomedical specialities including, although not exclusively: Cardiovascular system Cerebrovascular system Gastrointestinal tract and liver Genomic medicine Infection and immunity Inflammation Oncology Metabolism Endocrinology and nutrition Nephrology Circulation Respiratory system Vascular biology Molecular pathology.
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