Radiation induces premature chromatid separation via the miR-142-3p/Bod1 pathway in carcinoma cells

Pan, Dong; Du, Yarong; Ren, Zhen; Chen, Yaxiong; Li, Xiao Man; Wang, Jufang; Hu, Burong

doi:10.18632/oncotarget.11080

Cited by 15 publications

(16 citation statements)

References 57 publications

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“…Here, we found that miR-142-3p plays a tumor inhibitor role in cell growth, Recently, efficient evidence demonstrated that miRNAs were involved in the modulation of the development of BC. The multiple roles of miRNAs in BC have been studied extensively, including molecular markers (Nassar, Nasr, & Talhouk, 2017) (Pan et al, 2016), melanoma (Tembe et al, 2015), and hepatocellular carcinoma (Hua, Liu, Liu, & Wu, 2018). On the contrary, it was deemed to act as an oncogene in non-small-cell lung cancer (Lei et al, 2014) and T-cell acute lymphoblastic leukemia (Lv et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

MiR‐142‐3p functions as a tumor suppressor by targeting RAC1/PAK1 pathway in breast cancer

Pan

et al. 2019

Journal Cellular Physiology

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MicroRNA -142-3p (miR-142-3p) was previously investigated in various cancers, whereas, itʼs role in breast cancer (BC) remains far from understood. In this study, we found that miR-142-3p was markedly decreased both in cell lines and BC tumor tissues. Elevated miR-142-3p expression suppressed growth and metastasis of BC cell lines via gain-of-function assay in vitro and in vivo. Mechanistically, miR-142-3p could regulate the ras-related C3 botulinum toxin substrate 1 (RAC1) expression in protein level, which simultaneously suppressed the epithelial-to-mesenchymal transition related protein levels and the activity of PAK1 phosphorylation, respectively. In addition, rescue experiments revealed RAC1 overexpression could reverse tumorsuppressive role of miR-142-3p. Our results showed miR-142-3p could function as a tumor suppressor via targeting RAC1/PAK1 pathway in BC, suggesting a potent therapeutic target for BC treatment. K E Y W O R D Sbreast cancer, miR-142-3p, PAK1, RAC1

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Section: Discussionmentioning

confidence: 99%

MiR‐142‐3p functions as a tumor suppressor by targeting RAC1/PAK1 pathway in breast cancer

Pan

et al. 2019

Journal Cellular Physiology

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“…Reports have identified several autophagy-related miRNAs (e.g., miR-30a, miR-101, miR-181a and miR-375) that decrease autophagic activity to increase the sensitivity of tumour cells to chemotherapeutic or molecular-targeted agents. MiR-142-3p, which is located in human chromosome17q22, has been reported to serve as both an oncogene and a tumour suppressor in multiple human cancers 19 – 22 . However, the regulatory role of miR-142-3p in sorafenib resistance in HCC cells and the possible mechanism underlying this role are unclear.…”

Section: Introductionmentioning

confidence: 99%

PU.1/microRNA-142-3p targets ATG5/ATG16L1 to inactivate autophagy and sensitize hepatocellular carcinoma cells to sorafenib

et al. 2018

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Sorafenib is currently the only systemic agent approved for treatment of advanced hepatocellular carcinoma (HCC). However, intrinsic and acquired resistance to sorafenib remains a great challenge with respect to improving the prognoses of patients with HCC. The cyto-protective functions of autophagy have been suggested as a potential mechanism by which chemoresistance or targeted drug resistance occurs in tumour cells. In the present study, miR-142-3p was identified as a novel autophagy-regulating microRNA (miRNA) that plays a vital role in sorafenib resistance in HCC cells. Gain- and loss-of-function assays revealed that ectopic miR-142-3p upregulation sensitized HCC cells to sorafenib by reducing sorafenib-induced autophagy, enhancing sorafenib-induced apoptosis and inhibiting cell growth, whereas miR-142-3p inhibition exerted contrasting effects. Bioinformatics analysis and luciferase reporter and rescue assays showed that autophagy-related 5 (ATG5) and autophagy-related 16-like 1 (ATG16L1) are potential targets through which miR-142-3p regulates autophagy inhibition. Furthermore, we verified that PU.1 regulated the expression of miR-142-3p in conjunction with our cellular experiments and the related results in the literature. Our findings show that targeting the PU.1–miR-142-3p–ATG5/ATG16L1 axis may be a useful therapeutic strategy for preventing cyto-protective autophagy to overcome sorafenib resistance.

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“…Depletion of Bod1 from HeLa cells leads to premature loss of phosphorylation on several kinetochore proteins, including MCAK and CENP-U/PBIP1, due to unregulated activity of PP2A-B56, which causes an increase in aberrant chromosome attachments and defective chromosome segregation. Bod1 has also recently been shown to alleviate premature, radiation-induced chromatid separation in human lung and renal cell carcinoma cells, protecting against genomic instability [ 21 ]. Bod1, together with CIP2A [ 22 ], FAM122A [ 23 ], I1PP2A/ANP32A [ 24 ], I2PP2A/SET [ 25 ], TIP [ 26 ] and Arpp-19/Ensa [ 27 , 28 ], forms part of a growing family of PP2A inhibitors that have important roles in supporting cell division.…”

Section: Introductionmentioning

confidence: 99%

The Ndc80 complex targets Bod1 to human mitotic kinetochores

et al. 2017

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Regulation of protein phosphatase activity by endogenous protein inhibitors is an important mechanism to control protein phosphorylation in cells. We recently identified Biorientation defective 1 (Bod1) as a small protein inhibitor of protein phosphatase 2A containing the B56 regulatory subunit (PP2A-B56). This phosphatase controls the amount of phosphorylation of several kinetochore proteins and thus the establishment of load-bearing chromosome-spindle attachments in time for accurate separation of sister chromatids in mitosis. Like PP2A-B56, Bod1 directly localizes to mitotic kinetochores and is required for correct segregation of mitotic chromosomes. In this report, we have probed the spatio-temporal regulation of Bod1 during mitotic progression. Kinetochore localization of Bod1 increases from nuclear envelope breakdown until metaphase. Phosphorylation of Bod1 at threonine 95 (T95), which increases Bod1's binding to and inhibition of PP2A-B56, peaks in prometaphase when PP2A-B56 localization to kinetochores is highest. We demonstrate here that kinetochore targeting of Bod1 depends on the outer kinetochore protein Ndc80 and not PP2A-B56. Crucially, Bod1 depletion functionally affects Ndc80 phosphorylation at the N-terminal serine 55 (S55), as well as a number of other phosphorylation sites within the outer kinetochore, including Knl1 at serine 24 and 60 (S24, S60), and threonine T943 and T1155 (T943, T1155). Therefore, Ndc80 recruits a phosphatase inhibitor to kinetochores which directly feeds forward to regulate Ndc80, and Knl1 phosphorylation, including sites that mediate the attachment of microtubules to kinetochores.

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Radiation induces premature chromatid separation via the miR-142-3p/Bod1 pathway in carcinoma cells

Cited by 15 publications

References 57 publications

MiR‐142‐3p functions as a tumor suppressor by targeting RAC1/PAK1 pathway in breast cancer

MiR‐142‐3p functions as a tumor suppressor by targeting RAC1/PAK1 pathway in breast cancer

PU.1/microRNA-142-3p targets ATG5/ATG16L1 to inactivate autophagy and sensitize hepatocellular carcinoma cells to sorafenib

The Ndc80 complex targets Bod1 to human mitotic kinetochores

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