LMW cyclin E and its novel catalytic partner CDK5 are therapeutic targets and prognostic biomarkers in salivary gland cancers.
LMW cyclin E and its novel catalytic partner CDK5 are therapeutic targets and prognostic biomarkers in salivary gland cancers.
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DOI：
10.1038/s41389-021-00324-z
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发表时间：
2021-05-14
期刊：
影响因子：
6.2
通讯作者：
Keyomarsi K
中科院分区：
文献类型：
--
作者：
Lulla AR;Akli S;Karakas C;Ha MJ;Fowlkes NW;Mitani Y;Bui T;Wang J;Rao X;Hunt KK;Meijer L;El-Naggar AK;Keyomarsi K
唾液腺癌（SGCs）是一种罕见但具有侵袭性的恶性肿瘤，具有显著的组织学异质性，这使得预测预后和开发靶向治疗具有挑战性。大多数患者，局部复发和/或远处转移是常见的，全身治疗对生存的影响很小。因此，确定新的治疗靶点，也可以用作多种组织学亚型SGCs复发的预测因子，是一个尚未满足需求的领域。在这项研究中，我们建立了一种新的SGC转基因小鼠模型，有效地概括了人类SGC的主要组织学亚型（腮腺腺癌）。CDK2敲除（KO）小鼠与mmtv -低分子量形式的细胞周期素E （LMW-E）小鼠杂交，产生了SGC转基因小鼠模型，该模型出现在唾液腺的腮腺区域，类似于人类SGC的常见起源部位。为了鉴定LMW-E不依赖CDK2的催化伙伴，我们使用表达LMW-E的细胞系进行质谱分析，并随后在拉下试验中进行生化验证。这些研究表明，在缺乏CDK2的情况下，LMW-E优先与CDK5结合。利用siRNA分子靶向CDK5，抑制过表达LMW-E的人SGCs的细胞增殖。我们还提供了临床证据，证明lw -e /CDK5共表达与降低人类SGC的无复发生存率有显著关联。免疫组织化学分析了424例患者的LMW-E和CDK5，这些患者代表了人类唾液癌的四种主要组织学亚型（Aci、AdCC、MEC和SDC），结果显示LMW-E和CDK5在70%的患者中一致表达（阳性/阳性或阴性/阴性）。无论这些肿瘤的组织学分类如何，LMW-E/CDK5的共表达（均为阳性）都有力地预测了复发的可能性。总之，我们的研究结果表明，CDK5是一种新的、可靶向的生物标志物，可用于治疗以LMW-E过表达肿瘤为表现的SGC患者。
Salivary gland cancers (SGCs) are rare yet aggressive malignancies with significant histological heterogeneity, which has made prediction of prognosis and development of targeted therapies challenging. In majority of patients, local recurrence and/or distant metastasis are common and systemic treatments have minimal impact on survival. Therefore, identification of novel targets for treatment that can also be used as predictors of recurrence for multiple histological subtypes of SGCs is an area of unmet need. In this study, we developed a novel transgenic mouse model of SGC, efficiently recapitulating the major histological subtype (adenocarcinomas of the parotid gland) of human SGC. CDK2 knock out (KO) mice crossed with MMTV-low molecular weight forms of cyclin E (LMW-E) mice generated the transgenic mouse models of SGC, which arise in the parotid region of the salivary gland, similar to the common site of origin seen in human SGCs. To identify the CDK2 independent catalytic partner(s) of LMW-E, we used LMW-E expressing cell lines in mass spectrometric analysis and subsequent biochemical validation in pull down assays. These studies revealed that in the absence of CDK2, LMW-E preferentially binds to CDK5. Molecular targeting of CDK5, using siRNA, resulted in inhibition of cell proliferation of human SGCs overexpressing LMW-E. We also provide clinical evidence of significant association of LMW-E/CDK5 co-expression and decreased recurrence free survival in human SGC. Immunohistochemical analysis of LMW-E and CDK5 in 424 patients representing each of the four major histological subtypes of human salivary cancers (Aci, AdCC, MEC, and SDC) revealed that LMW-E and CDK5 are concordantly (positive/positive or negative/negative) expressed in 70% of these patients. The co-expression of LMW-E/CDK5 (both positive) robustly predicts the likelihood of recurrence, regardless of the histological classification of these tumors. Collectively, our results suggest that CDK5 is a novel and targetable biomarker for the treatment of patients with SGC presenting with LMW-E overexpressing tumors.
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影响因子：
30.8
作者：
Ho, Allen S.;Kannan, Kasthuri;Roy, David M.;Morris, Luc G. T.;Ganly, Ian;Katabi, Nora;Ramaswami, Deepa;Walsh, Logan A.;Eng, Stephanie;Huse, Jason T.;Zhang, Jianan;Dolgalev, Igor;Huberman, Kety;Heguy, Adriana;Viale, Agnes;Drobnjak, Marija;Leversha, Margaret A.;Rice, Christine E.;Singh, Bhuvanesh;Iyer, N. Gopalakrishna;Leemans, C. Rene;Bloemena, Elisabeth;Ferris, Robert L.;Seethala, Raja R.;Gross, Benjamin E.;Liang, Yupu;Sinha, Rileen;Peng, Luke;Raphael, Benjamin J.;Turcan, Sevin;Gong, Yongxing;Schultz, Nikolaus;Kim, Seungwon;Chiosea, Simion;Shah, Jatin P.;Sander, Chris;Lee, William;Chan, Timothy A.
通讯作者：
Chan, Timothy A.
影响因子：
11.5
作者：
Kettner, Nicole M.;Vijayaraghavan, Smruthi;Keyomarsi, Khandan
通讯作者：
Keyomarsi, Khandan
影响因子：
11.2
作者：
Akli, Said;Van Pelt, Carolyn S.;Keyomarsi, Khandan
通讯作者：
Keyomarsi, Khandan
影响因子：
3
作者：
Conroy, Andrew;Stockett, David E.;Hawtin, Rachael Elizabeth
通讯作者：
Hawtin, Rachael Elizabeth
影响因子：
--
作者：
Alexander A;Karakas C;Chen X;Carey JP;Yi M;Bondy M;Thompson P;Cheung KL;Ellis IO;Gong Y;Krishnamurthy S;Alvarez RH;Ueno NT;Hunt KK;Keyomarsi K
通讯作者：
Keyomarsi K