LncRNA IPW inhibits growth of ductal carcinoma in situ by downregulating ID2 through miR-29c.
LncRNA IPW inhibits growth of ductal carcinoma in situ by downregulating ID2 through miR-29c.
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DOI：
10.1186/s13058-022-01504-4
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发表时间：
2022-01-25
期刊：
影响因子：
--
通讯作者：
Watabe K
中科院分区：
文献类型：
--
作者：
Deshpande RP;Sharma S;Liu Y;Pandey PR;Pei X;Wu K;Wu SY;Tyagi A;Zhao D;Mo YY;Watabe K
乳腺导管原位癌（DCIS）是一种非侵袭性病变，有发展为恶性的倾向。目前，尚不清楚哪些病变可能进展为侵袭性形式。在这项研究中，我们的目的是确定参与DCIS生长的关键lncRNA。我们采用疾病相关的lncProfiler阵列来识别DCIS样本和匹配对照样本中的IPW，并在三种DCIS非致瘤细胞系中验证观察结果。此外，我们研究了IPW的作用机制和下游信号在体外和体内测定。重要的是，我们筛选了含有390种天然化合物的文库，以鉴定选择性抑制IPW低DCIS细胞的候选化合物。我们确定lncRNA IPW作为一种新的肿瘤抑制因子，对抑制DCIS生长至关重要。IPW在DCIS细胞中的异位表达强烈抑制细胞增殖、集落形成和细胞周期进程，而在原代乳腺细胞中沉默IPW促进其生长。此外，异位表达IPW的细胞的正交植入表现出体内肿瘤生长减少。从机制上讲，IPW通过促进H3 K4 me 3在其启动子区的富集，表观遗传学上增强了miR-29 c的表达。此外，我们发现miR-29 c负调控干细胞促进基因ID 2，并降低DCIS细胞的自我更新能力。重要的是，我们筛选了一个包含390种天然化合物的文库，并将丰卡霉素鉴定为选择性抑制IPW低表达的DCIS生长的化合物，而它不影响IPW高表达的DCIS。丰霉素还抑制与自我更新能力相关的基因，并抑制体内DCIS生长。我们的研究结果揭示了IPW-miR-29 c-ID 2轴在DCIS形成中的关键作用，并提示了丰卡霉素治疗DCIS的潜在临床用途。在线版本包含补充材料，可通过10.1186/s13058-022-01504-4获得。
Ductal carcinoma in situ (DCIS) of breast is the noninvasive lesion that has propensity to progress to the malignant form. At present, it is still unknown which lesions can potentially progress to invasive forms. In this study, we aimed to identify key lncRNAs involved in DCIS growth. We employ disease-related lncProfiler array to identify IPW in specimens of DCIS and matching control samples and validate the observations in three DCIS-non-tumorigenic cell lines. Further, we examine the mechanism of IPW action and the downstream signaling in in vitro and in vivo assays. Importantly, we screened a library containing 390 natural compounds to identify candidate compound selectively inhibiting IPW low DCIS cells. We identified lncRNA IPW as a novel tumor suppressor critical for inhibiting DCIS growth. Ectopic expression of IPW in DCIS cells strongly inhibited cell proliferation, colony formation and cell cycle progression while silencing IPW in primary breast cells promoted their growth. Additionally, orthotropic implantation of cells with ectopic expression of IPW exhibited decreased tumor growth in vivo. Mechanistically, IPW epigenetically enhanced miR-29c expression by promoting H3K4me3 enrichment in its promoter region. Furthermore, we identified that miR-29c negatively regulated a stemness promoting gene, ID2, and diminished self-renewal ability of DCIS cells. Importantly, we screened a library containing 390 natural compounds and identified toyocamycin as a compound that selectively inhibited the growth of DCIS with low expression of IPW, while it did not affect DCIS with high IPW expression. Toyocamycin also suppressed genes associated with self-renewal ability and inhibited DCIS growth in vivo. Our findings revealed a critical role of the IPW-miR-29c-ID2 axis in DCIS formation and suggested potential clinical use of toyocamycin for the treatment of DCIS. The online version contains supplementary material available at 10.1186/s13058-022-01504-4.
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影响因子：
4
作者：
Carraro DM;Elias EV;Andrade VP
通讯作者：
Andrade VP
miR-29c 通过靶向 TIMP3/STAT1/FOXO1 通路在乳腺癌中发挥抑制作用。
影响因子：
5.7
作者：
Li W;Yi J;Zheng X;Liu S;Fu W;Ren L;Li L;Hoon DSB;Wang J;Du G
通讯作者：
Du G
DOI：
10.5317/wjog.v5.i2.150
发表时间：
2016-05-10
期刊：
World journal of obstetrics and gynecology
影响因子：
--
作者：
Lo PK;Wolfson B;Zhou Q
通讯作者：
Zhou Q
影响因子：
11.2
作者：
Jedeszko C;Victor BC;Podgorski I;Sloane BF
通讯作者：
Sloane BF
DOI：
10.1007/978-981-10-5203-3_2
发表时间：
2017-01-01
期刊：
LONG NON CODING RNA BIOLOGY
影响因子：
--
作者：
Akhade, Vijay Suresh;Pal, Debosree;Kanduri, Chandrasekhar
通讯作者：
Kanduri, Chandrasekhar