microRNA-99a-5p induces cellular senescence in gemcitabine-resistant bladder cancer by targeting SMARCD1.
microRNA-99a-5p induces cellular senescence in gemcitabine-resistant bladder cancer by targeting SMARCD1.
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DOI：
10.1002/1878-0261.13192
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发表时间：
2022-03
影响因子：
6.6
通讯作者：
Yoshino H
中科院分区：
文献类型：
--
作者：
Tamai M;Tatarano S;Okamura S;Fukumoto W;Kawakami I;Osako Y;Sakaguchi T;Sugita S;Yonemori M;Yamada Y;Nakagawa M;Enokida H;Yoshino H
晚期膀胱癌患者通常使用联合化疗药物（包括吉西他滨）进行治疗，但由于获得耐药性，效果有限。因此，在本研究中，我们研究了吉西他滨耐药的机制。首先，建立吉西他滨耐药细胞，并在体外和体内证实耐药性。进行小RNA测序分析以搜索参与吉西他滨耐药的miRNA。选择作为候选miRNA的miR-99 a-5 p与其亲本细胞相比下调。在功能获得研究中，miR-99 a-5 p抑制细胞活力并恢复对吉西他滨的敏感性。进行RNA测序分析以找到miR-99 a-5 p的靶基因。SMARCD 1被选为候选基因。双荧光素酶报告基因分析表明，miR-99 a-5 p直接调控SMARD 1。使用si-RNA进行的功能丧失研究显示细胞功能受到抑制，吉西他滨敏感性恢复。miR-99 a-5 p过表达和SMARD 1敲低也抑制了体内吉西他滨耐药细胞。此外，β-半乳糖苷酶染色显示miR-99 a-5 p诱导和SMARD 1抑制有助于细胞衰老。总之，肿瘤抑制性miR-99 a-5 p通过靶向SMARD 1诱导吉西他滨耐药膀胱癌细胞的细胞衰老。在此，我们通过体外逐步暴露于吉西他滨建立了吉西他滨耐药膀胱癌（BC）细胞系。我们还在异种移植小鼠模型中证实了吉西他滨耐药性。我们的数据显示，在细胞衰老抑制后，吉西他滨耐药BC细胞中miR-99 a-5 p下调，miR-99 a-5 p靶点SMARD 1上调。总之，miR-99 a-5 p通过靶向SMARD 1诱导吉西他滨耐药BC的细胞衰老。
Patients with advanced bladder cancer are generally treated with a combination of chemotherapeutics, including gemcitabine, but the effect is limited due to acquisition of drug resistance. Thus, in this study, we investigated the mechanism of gemcitabine resistance. First, gemcitabine‐resistant cells were established and resistance confirmed in vitro and in vivo. Small RNA sequencing analyses were performed to search for miRNAs involved in gemcitabine resistance. miR‐99a‐5p, selected as a candidate miRNA, was downregulated compared to its parental cells. In gain‐of‐function studies, miR‐99a‐5p inhibited cell viabilities and restored sensitivity to gemcitabine. RNA sequencing analysis was performed to find the target gene of miR‐99a‐5p. SMARCD1 was selected as a candidate gene. Dual‐luciferase reporter assays showed that miR‐99a‐5p directly regulated SMARCD1. Loss‐of‐function studies conducted with si‐RNAs revealed suppression of cell functions and restoration of gemcitabine sensitivity. miR‐99a‐5p overexpression and SMARCD1 knockdown also suppressed gemcitabine‐resistant cells in vivo. Furthermore, β‐galactosidase staining showed that miR‐99a‐5p induction and SMARCD1 suppression contributed to cellular senescence. In summary, tumor‐suppressive miR‐99a‐5p induced cellular senescence in gemcitabine‐resistant bladder cancer cells by targeting SMARCD1. Here, we established gemcitabine‐resistant bladder cancer (BC) cell line by stepwise exposure to gemcitabine in vitro. We also confirmed gemcitabine resistance in a xenograft mouse model. Our data showed downregulation of miR‐99a‐5p and upregulation of the miR‐99a‐5p target SMARCD1 in gemcitabine‐resistant BC cells, following cellular senescence inhibition. In summary, miR‐99a‐5p induced cellular senescence in gemcitabine‐resistant BC by targeting SMARCD1.
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DOI：
10.1515/9783110470734-007
发表时间：
2018-01-01
期刊：
METALLO-DRUGS: DEVELOPMENT AND ACTION OF ANTICANCER AGENTS
影响因子：
--
作者：
Casini, Angela;Sun, Raymond Wai-Yin;Ott, Ingo
通讯作者：
Ott, Ingo
影响因子：
3.7
作者：
Dhayat SA;Mardin WA;Seggewiß J;Ströse AJ;Matuszcak C;Hummel R;Senninger N;Mees ST;Haier J
通讯作者：
Haier J
影响因子：
5.2
作者：
Hong, Sen;Yan, Zhenkun;Li, Shiquan
通讯作者：
Li, Shiquan
DOI：
10.1083/jcb.201009094
发表时间：
2011-02-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Rodier F;Campisi J
通讯作者：
Campisi J
影响因子：
2
作者：
Cao, Jingyi;Wang, Qichao;Wang, Qian
通讯作者：
Wang, Qian