Suppression of KIF3A inhibits triple negative breast cancer growth and metastasis by repressing Rb‐E2F signaling and epithelial‐mesenchymal transition

Wang, Weilin; Zhang, Runze; Wang, Xiao; Wang, Ning; Zhao, Jing; Wei, Zhimin; Xiang, Fenggang; Wang, Chengqin

doi:10.1111/cas.14324

Cited by 23 publications

(28 citation statements)

References 55 publications

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“…In our study, we performed Western blotting and observed that the expression of the EMT-related proteins N-cadherin and Vimentin was downregulated after overexpressing KIF3A. However, in triple-negative breast cancer, knockdown of KIF3A expression reduced Vimentin protein expression and enhanced E-cadherin protein expression, which is contrary to our conclusion [13].…”

Section: Discussioncontrasting

confidence: 93%

“…To date, KIF3A has been reported to function as a tumour promoter and to enhance the proliferation and metastasis of prostate cancer, triple-negative breast cancer, and bladder cancer [12][13][14]. Additionally, silencing the KIF3A gene in thyroid cancer cell lines leads to defective ciliogenesis, which in turn promotes mitochondria-dependent apoptosis [15].…”

Section: Introductionmentioning

confidence: 99%

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KIF3A Inhibits NPC Proliferation, Migration and Invasion By Interacting With β-Catenin To Suppress Its Nuclear Accumulation

Meng

Hongbing

et al. 2021

Preprint

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Background Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumour that is prevalent in Southern China and other Southeast Asian countries. In previous studies, Kinesin Family Member 3A (KIF3A) was shown to play a dual role in cancers. However, the biological role of KIF3A in NPC and the underlying mechanism have not been reported. Methods The KIF3A mRNA and protein expressions in NPC were analyzed by qRT-PCR (Quantitative real-time polymerase chain reaction), Western blotting and immunohistochemistry. CCK-8, EDU incorporation assay, Colony formation, cell cycle assay, Wound-Healing Assay, Transwell verified KIF3A regulates the proliferation, migration, invasion of NPC cells. The in vivo effect of KIF3A on proliferation was elucidated with a xenograft mouse model. COIP (Co-immunoprecipitation) assay showed KIF3A interacts with β-catenin. Confocal microscopy colocalization assay confirmed colocalization of KIF3A and β-catenin in NPC cells. Nuclear and cytoplasmic extraction assays were performed to analyze the distribution of β-catenin in the nuclei and cytoplasm. Results In this study, we found that KIF3A interacts with β-catenin, suppressing the intranuclear aggregation of β-catenin, then inactivating the Wnt/β-catenin signaling pathway as well as the downstream cell cycle factors and EMT signal to inhibit NPC proliferation, migration, and invasion. Conclusions These findings suggest that KIF3A interacts with β-catenin and attenuates the malignant progression of NPC by inhibiting β-catenin intranuclear aggregation. KIF3A may be a promising therapeutic target for NPC patients.

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Section: Discussioncontrasting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

KIF3A Inhibits NPC Proliferation, Migration and Invasion By Interacting With β-Catenin To Suppress Its Nuclear Accumulation

Meng

Hongbing

et al. 2021

Preprint

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“… 30 Studies have demonstrated that the RB/E2F pathway is critical for control of the cell cycle and tumor progression. 31 , 32 pRB is phosphorylated on S807/811 during the S phase, and phosphorylation of RB's C-terminal serine (S795) destabilizes the interaction between RB and the E2F1-DP1 heterodimer. 33 , 34 Upon phosphorylation of RB at S795 and S807/811, downstream targets of E2F, such as CCNA2 , CDK1 , and MCM2 , will be transcriptionally activated.…”

Section: Discussionmentioning

confidence: 99%

RNA-binding protein MEX3A controls G1/S transition via regulating the RB/E2F pathway in clear cell renal cell carcinoma

Qiu

Meng

Cao

et al. 2022

Molecular Therapy - Nucleic Acids

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MEX3A is an RNA-binding protein that mediates mRNA decay through binding to 3′ untranslated regions. However, its role and mechanism in clear cell renal cell carcinoma remain unknown. In this study, we found that MEX3A expression was transcriptionally activated by ETS1 and upregulated in clear cell renal cell carcinoma. Silencing MEX3A markedly reduced clear cell renal cell carcinoma cell proliferation in vitro and in vivo . Inhibiting MEX3A induced G1/S cell-cycle arrest. Gene set enrichment analysis revealed that E2F targets are the central downstream pathways of MEX3A. To identify MEX3A targets, systematic screening using enhanced cross-linking and immunoprecipitation sequencing, and RNA-immunoprecipitation sequencing assays were performed. A network of 4,000 genes was identified as potential targets of MEX3A. Gene ontology analysis of upregulated genes bound by MEX3A indicated that negative regulation of the cell proliferation pathway was highly enriched. Further assays indicated that MEX3A bound to the CDKN2B 3′ untranslated region, promoting its mRNA degradation. This leads to decreased levels of CDKN2B and an uncontrolled cell cycle in clear cell renal cell carcinoma, which was confirmed by rescue experiments. Our findings revealed that MEX3A acts as a post-transcriptional regulator of abnormal cell-cycle progression in clear cell renal cell carcinoma.

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“…The above experimental data confirmed that tRF-17-79MP9PP could inhibit breast malignant activities of cancer cells, so its target gene should be associated with tumor cell invasion, metastasis or proliferation. Based on the rationale, four candidate genes (THBS1, KIF3A, RAB10, RFX5) were selected after a literature review (18)(19)(20)(21)(22)(23). Further analysis revealed that tRF-17-79MP9PP had "seed sequences", which may bind to the 3'UTR of the four candidate genes according to TargetScan and miRanda programs (Figure 4B).…”

Section: Go and Kegg Enrichment Analysis Of Trf-17-79mp9pp Target Genesmentioning

confidence: 99%

tRNA-Derived Fragment tRF-17-79MP9PP Attenuates Cell Invasion and Migration via THBS1/TGF-β1/Smad3 Axis in Breast Cancer

Zheng

et al. 2021

Front. Oncol.

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tRNA derivatives have been identified as a new kind of potential biomarker for cancer. Previous studies have identified that there were 30 differentially expressed tRNAs derivatives in breast cancer tissue with the high-throughput sequencing technique. This study aimed to investigate the possible biological function and mechanism of tRNA derivatives in breast cancer cells. One such tRF, a 5’-tRF fragment of tRF-17-79MP9PP (tRF-17) was screened in this study, which is processed from the mature tRNA-Val-AAC and tRNA-Val-CAC. tRF-17 with significantly low expression in breast cancer tissues and serum. The level of tRF-17 differentiated breast cancer from healthy controls with sensitivity of 70.4% and specificity of 68.4%. Overexpression of tRF-17 suppressed cells malignant activity. THBS1 (Thrombospondin-1) as a downstream target of tRF-17, and reduction of THBS1 expression also partially recovered the effects of tRF-17 inhibition on breast cancer cell viability, invasion and migration. Besides, THBS1, TGF-β1, Smad3, p-Smad3 and epithelial-to-mesenchymal transition related genes N-cadherin, MMP3, MMP9 were markedly down-regulated in tRF-17 overexpressing cells. Moreover, tRF-17 attenuated the THBS1-mediated TGF-β1/Smad3 signaling pathway in breast cancer cells. In general, the tRF-17/THBS1/TGF-β1/smad3 axis elucidates the molecular mechanism of breast cancer cells invasion and migration and could lead to a potential therapeutic target for breast cancer.

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Suppression of KIF3A inhibits triple negative breast cancer growth and metastasis by repressing Rb‐E2F signaling and epithelial‐mesenchymal transition

Cited by 23 publications

References 55 publications

KIF3A Inhibits NPC Proliferation, Migration and Invasion By Interacting With β-Catenin To Suppress Its Nuclear Accumulation

KIF3A Inhibits NPC Proliferation, Migration and Invasion By Interacting With β-Catenin To Suppress Its Nuclear Accumulation

RNA-binding protein MEX3A controls G1/S transition via regulating the RB/E2F pathway in clear cell renal cell carcinoma

tRNA-Derived Fragment tRF-17-79MP9PP Attenuates Cell Invasion and Migration via THBS1/TGF-β1/Smad3 Axis in Breast Cancer

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