TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer.
TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer.
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TGFβ1 促进吉西他滨耐药性调节膀胱癌中的 lncRNA-LET/NF90/miR-145 信号轴
作者：
Zhuang J;Shen L;Yang L;Huang X;Lu Q;Cui Y;Zheng X;Zhao X;Zhang D;Huang R;Guo H;Yan J
膀胱癌（ubc）患者经常出现高肿瘤复发率，需要预后和药物反应的生物标志物。化疗耐药和随后的癌症复发是由肿瘤起始细胞亚群，即癌症干细胞（CSCs）驱动的。然而，化疗诱导CSCs富集的潜在分子机制在很大程度上仍不清楚。在本研究中，我们发现在吉西他滨治疗期间，lncRNA-Low Expression In Tumor （lncRNA-LET）在化疗耐药的UBC中下调，并伴有CSC群体的富集。lncRNA-LET的敲低增加了UBC细胞的干细胞性，而lncRNA-LET的强制表达延迟了吉西他滨诱导的肿瘤复发。此外，通过lncRNA-LET启动子中的SMAD结合元件（SBE），吉西他滨治疗诱导的TGFβ/SMAD信号过度激活直接抑制了lncRNA-LET。因此，lncRNA-LET的减少增加了NF90蛋白的稳定性，这反过来又抑制了miR-145的生物发生，随后导致CSCs的积累，干细胞标记物HMGA2和KLF4的水平升高证明了这一点。用临床相关的TGFβRI特异性抑制剂LY2157299治疗吉西他滨耐药异种移植物，使其对吉西他滨增敏，并显著降低体内致瘤性。值得注意的是，tgf - β1的过表达，结合lncRNA-LET和miR-145水平的降低，预测了UBC患者的不良预后。总之，我们证明了吉西他滨诱导的tgf - β1失调的lncRNA-LET/NF90/miR-145轴通过增强癌细胞的干细胞性来促进UBC的化疗耐药。tgf - β1/lncRNA-LET/miR-145的联合变化为UBC预后提供了新的分子预后标志物。因此，靶向该轴可能是治疗UBC患者的一种有希望的治疗方法。
High tumor recurrence is frequently observed in patients with urinary bladder cancers (UBCs), with the need for biomarkers of prognosis and drug response. Chemoresistance and subsequent recurrence of cancers are driven by a subpopulation of tumor initiating cells, namely cancer stem-like cells (CSCs). However, the underlying molecular mechanism in chemotherapy-induced CSCs enrichment remains largely unclear. In this study, we found that during gemcitabine treatment lncRNA-Low Expression in Tumor (lncRNA-LET) was downregulated in chemoresistant UBC, accompanied with the enrichment of CSC population. Knockdown of lncRNA-LET increased UBC cell stemness, whereas forced expression of lncRNA-LET delayed gemcitabine-induced tumor recurrence. Furthermore, lncRNA-LET was directly repressed by gemcitabine treatment-induced overactivation of TGFβ/SMAD signaling through SMAD binding element (SBE) in the lncRNA-LET promoter. Consequently, reduced lncRNA-LET increased the NF90 protein stability, which in turn repressed biogenesis of miR-145 and subsequently resulted in accumulation of CSCs evidenced by the elevated levels of stemness markers HMGA2 and KLF4. Treatment of gemcitabine resistant xenografts with LY2157299, a clinically relevant specific inhibitor of TGFβRI, sensitized them to gemcitabine and significantly reduced tumorigenecity in vivo. Notably, overexpression of TGFβ1, combined with decreased levels of lncRNA-LET and miR-145 predicted poor prognosis in UBC patients. Collectively, we proved that the dysregulated lncRNA-LET/NF90/miR-145 axis by gemcitabine-induced TGFβ1 promotes UBC chemoresistance through enhancing cancer cell stemness. The combined changes in TGFβ1/lncRNA-LET/miR-145 provide novel molecular prognostic markers in UBC outcome. Therefore, targeting this axis could be a promising therapeutic approach in treating UBC patients.
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影响因子：
11.2
作者：
Ho PL;Lay EJ;Jian W;Parra D;Chan KS
通讯作者：
Chan KS
影响因子：
11.2
作者：
Adorno-Cruz V;Kibria G;Liu X;Doherty M;Junk DJ;Guan D;Hubert C;Venere M;Mulkearns-Hubert E;Sinyuk M;Alvarado A;Caplan AI;Rich J;Gerson SL;Lathia J;Liu H
通讯作者：
Liu H
DOI：
10.1073/pnas.0906549106
发表时间：
2009-08-18
影响因子：
11.1
作者：
Chan, Keith Syson;Espinosa, Inigo;Weissman, Irving L.
通讯作者：
Weissman, Irving L.
影响因子：
11.2
作者：
Chien, Chian-Shiu;Wang, Mong-Lien;Chiou, Shih-Hwa
通讯作者：
Chiou, Shih-Hwa
长非编码 RNA MEG3 有助于人肺腺癌的顺铂耐药性。
影响因子：
3.7
作者：
Liu J;Wan L;Lu K;Sun M;Pan X;Zhang P;Lu B;Liu G;Wang Z
通讯作者：
Wang Z