miR551b Regulates Colorectal Cancer Progression by Targeting the ZEB1 Signaling Axis

Kim, Kwang Seock; Jeong, Dongjun; Sari, Ita Novita; Wijaya, Yoseph Toni; Jun, Nayoung; Lee, Sanghyun; Yang, Ying; Kwon, Hyog Young

doi:10.3390/cancers11050735

Cited by 5 publications

(1 citation statement)

References 32 publications

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“…В исследованиях показано, что убиквитинконъюгированный энзим E2 C (UBE2C) функционирует как онкоген, промотирующий ЭМП путем прямого влияния на 5′-UTR транскрипт, кодирующий ZEB1 [18]. В дополнение к этому, экспрессия ZEB1 регулируется разнообразными микроРНК на посттранскрипционном уровне [19][20][21]. Установлено, что семейство микроРНК miR-200 (miR-141, miR-200a и miR-200c) усиливает деградацию мРНК ZEB1 путем прямого связывания 3′-UTR.…”

Section: ингибирование Cdk 4/6 как стратегия блокирования эпителиально-мезенхимального перехода и образования траспортной формы опухолевоunclassified

Role of pre-metastatic niche in organ specificity of breast cancer metastasis. Influence on metastatic potential as a basis for CDK4/6-inhibition efficacy in early therapy of disseminated hormone-receptor-positive disease

et al. 2021

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Influencing the pre-metastatic niche is a very perspective cancer treatment strategy in order of preventing metastases formation. It was found that bone marrow progenitor cells and tumor cells secreting biological compounds are key components in the formation of the pre-metastatic niche. Myeloid suppressor cells (MSCs) are the main type of bone marrow cells in pre-metastatic niches. At the same time, tumor-associated chronic inflammation induces the expression of proinflammatory cytokines triggering myeloid cells differentiation into myeloid suppressor cells. When circulating tumor cells enter the circulatory channel, their interaction with immune cells is observed, which additionally influences the pre-metastatic site preparation. Studies have shown that the entire spectrum of immune cells is capable of influencing the metastasis formation by circulating tumor cells. The epithelialmesenchymal transition with the tumor cell transporting form appearence was found to be related to the function of the ZEB1 protein. Its activity is regulated by numerous signaling mechanisms at the transcriptional level, including TGFβ, Wnt and Notch. This initiates epithelial-mesenchymal transition of breast cancer cells. Zhang Z.et al. proved that CDK4/6 blocking leads ZEB1 protein stability decreasing, preventing metastasis in breast cancer in vitro and in vivo. Moreover, USP51 deubiquitinase has been identified as a target of cyclin-dependent 4/6 kinases. At the molecular level, CDK4/6 phosphorylate and activates USP51, which then influences ZEB1 deubiquitination and stabilization. A positive correlation was demonstrated between the expression of p-RB (an indicator of CDK4/6 activity), p-USP51 and ZEB1 in breast cancer samples. Thus, the CDK4/6-USP51-ZEB1 axis may play a key role in the metastasis of breast cancer. In breast cancer cells, inhibition of CDK4/6 was shown to increase the expression of E-cadherin but decrease the expression of mesenchymal markers, reducing the migratory ability and invasiveness of breast cancer cell lines. This biological effect may also explain the clinical efficacy of the CDK4/6 inhibitor Abemaciclib in early-line therapy of metastatic breast cancer as well as in adjuvant combination hormone therapy for the prevention of metastatic lesions in patients at high risk of recurrence and progression in the MONARCH E study. Besides, there were no response predictors evaluated in trials investigating CDK4/6 in breast cancer treatment and it is unknown if there any differences in treatment response according to the metastatic site. The clinical cases demonstrate abemaciclib clinical efficacy in metastatic breast cancer treatment regardless of metastatic site.

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Role of pre-metastatic niche in organ specificity of breast cancer metastasis. Influence on metastatic potential as a basis for CDK4/6-inhibition efficacy in early therapy of disseminated hormone-receptor-positive disease

et al. 2021

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CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism

Zhang

et al. 2020

Sig Transduct Target Ther

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Tumor metastasis is the most common cause of cancer-related deaths, yet it remains poorly understood. The transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) is involved in the epithelial-to-mesenchymal transition (EMT) and plays a pivotal role in tumor metastasis. However, the underlying mechanisms of the posttranslational modification of ZEB1 remain largely unknown. Herein, we demonstrated that specific inhibition of CDK4/6 was able to block tumor metastasis of breast cancer by destabilizing the ZEB1 protein in vitro and in vivo. Mechanistically, we determined that the deubiquitinase USP51 is a bona fide target of CDK4/6. The phosphorylation and activation of USP51 by CDK4/6 is necessary to deubiquitinate and stabilize ZEB1. Moreover, we found a strong positive correlation between the expression of p-RB (an indicator of CDK4/6 activity), p-USP51 and ZEB1 in metastatic human breast cancer samples. Notably, the high expression of p-RB, p-USP51, and ZEB1 was significantly correlated with a poor clinical outcome. Taken together, our results provide evidence that the CDK4/6-USP51-ZEB1 axis plays a key role in breast cancer metastasis and could be a viable therapeutic target for the treatment of advanced human cancers.

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Dysregulation of miR-551b-5p and SETD2 Predicts Poor Prognosis and Promotes Migration and Invasion of Thyroid Cancers

Gao

Dong

Zheng

et al. 2023

EMIDDT

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Objective:: This study was to investigate the clinical significance of miR-551b-5p and SETD2 in thyroid cancers (TC) and their effects on the biological function of TC cells Methods:: The expression level of miR-551b-5p and SETD2 in tumor/nontumor tissues and TC cell lines was measured by quantitative real-time polymerase chain reaction (RT-qPCR). Subsequently, the relationship between miR-551b-5p or SETD2 expression and the clinicopathological feature was detected by Chi-square analysis. Kaplan-Meier and multivariate Cox regression analyses were used to assess their prognostic values. Finally, the regulatory effects of miR-551b-5p and SETD2 on the proliferation, migration and invasion ability of TC cells were detected by CCK-8 and Transwell assays. Results:: Compared with non-tumor groups, the expression of miR-551b-5p was significantly increased in patients' tissues and TC cell lines, while SETD2 mRNA expression was decreased. Patients with up-regulated miR-551b-5p or downregulated SETD2 mRNA in TC showed more positive lymph node metastasis and advanced TNM stage. High miR-551b-5p expression level and low SETD2 mRNA level were related to poor survival rate. miR-551b-5p and SETD2 might be potential prognostic biomarkers for TC. miR-551b-5p knockdown can inhibit cell proliferation, migration and invasion by targeting SETD2 Conclusion:: miR-551b-5p and SETD2 may be valuable prognostic biomarkers and new therapeutic targets for TC. result: Compared with all control groups, the expression of miR-551b-5p was significantly increased in 133 patients'' tissues and TC cell lines, while SETD2 mRNA expression was decreased. Patients with up-regulated miR-551b-5p and downregulated SETD2 mRNA in TC showed more positive lymph node metastasis and advanced TNM stage. High miR-551b-5p expression level and low SETD2 mRNA level were related to poor survival rate. miR-551b-5p and SETD2 might be potential prognostic biomarkers for TC. miR-551b-5p knockdown can inhibit cell migration and invasion by targeting SETD2. other: N/A

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miR551b Regulates Colorectal Cancer Progression by Targeting the ZEB1 Signaling Axis

Cited by 5 publications

References 32 publications

Role of pre-metastatic niche in organ specificity of breast cancer metastasis. Influence on metastatic potential as a basis for CDK4/6-inhibition efficacy in early therapy of disseminated hormone-receptor-positive disease

Role of pre-metastatic niche in organ specificity of breast cancer metastasis. Influence on metastatic potential as a basis for CDK4/6-inhibition efficacy in early therapy of disseminated hormone-receptor-positive disease

CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism

Dysregulation of miR-551b-5p and SETD2 Predicts Poor Prognosis and Promotes Migration and Invasion of Thyroid Cancers

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