TCF7 knockdown inhibits the imatinib resistance of chronic myeloid leukemia K562/G01 cells by neutralizing the Wnt/β‑catenin/TCF7/ABC transporter signaling axis

Zhang, Hui; Wang, Yonghong; Yang, Hao; Huang, Zhenglan; Wang, Xin; Feng, Wenli

doi:10.3892/or.2020.7869

Cited by 9 publications

(10 citation statements)

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“…1 D). The Wnt/β-catenin pathway signaling has been shown to propagates the initiation and progression of HLF [ 22 ], and TCF7 is essential for the typical WNT/β-catenin pathway [ 44 ]. However, the relationship between TCF7 and HLF pathogenesis is unclear and needs further study.…”

Section: Resultsmentioning

confidence: 99%

“…Transcription factor 7 (TCF7, also known as TCF1) is one of the members of the TCF/LEF transcription factor family and participates in the transcriptional regulation of Wnt/β-catenin signal [ 1 , 3 ]. Emerging evidence has shown that TCF7 is involved in tumorigenesis and development [ 2 , 35 , 44 ], sepsis-induced renal injury [ 39 ], heart development [ 40 ], and cardiac hypertrophy [ 26 ]. However, the roles and underlying mechanism of TCF7 in HLF have not been clarified.…”

Section: Introductionmentioning

confidence: 99%

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TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum

Duan

Qiu

et al. 2022

J Transl Med

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Background Hypertrophy of ligamentum flavum (HLF) is the mainly cause of lumbar spinal stenosis (LSS), but the precise mechanism of HLF formation has not been fully elucidated. Emerging evidence indicates that transcription factor 7 (TCF7) is the key downstream functional molecule of Wnt/β-catenin signaling, which participated in regulating multiple biological processes. However, the role and underlying mechanism of TCF7 in HLF is still unclear. Methods We used mRNAs sequencing analysis of human LF and subsequent confirmation with RT-qPCR, western blot and immunohistochemistry to identified the TCF7 in HLF tissues and cells. Then effect of TCF7 on HLF progression was investigated both in vitro and in vivo. Mechanically, chromatin immunoprecipitation, dual-luciferase reporter assays, and rescue experiments were used to validate the regulation of TCF7/SNAI2/miR-4306 feedback loop. Results Our results identified for first time that the TCF7 expression was obviously elevated in HLF tissues and cells compared with control, and also found that TCF7 expression had significant positive correlation with LF thickness and fibrosis score. Notably, TCF7 inhibition suppressed the hyper-proliferation and fibrosis phenotype of HLF cells in vitro and ameliorated progression of HLF in mice in vivo, whereas TCF7 overexpression promoted hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Our data further revealed that TCF7 interacted with SNAI2 promoter to transactivated the SNAI2 expression, thereby promoting hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Furthermore, miR-4036 negatively regulated by SNAI2 could negatively feedback regulate TCF7 expression by directly binding to TCF7 mRNA 3’-UTR, thus inhibiting the hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Conclusions Our study demonstrated that TCF7 inhibition could suppress HLF formation by modulating TCF7/SNAI2/miR-4306 feedback loop, which might be considered as a novel potential therapeutic target for HLF.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum

Duan

Qiu

et al. 2022

J Transl Med

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“…However, no distinct effect on IC-50 value was caught (Additional file 2 : Figure S2D). Previous investigations have linked the Wnt pathway with imatinib-resistance [ 34 , 35 ], the relevant markers including CTNNB1 and c-Myc were detected using a western blot assay, accordingly. The data demonstrated a discernible loss of both CTNNB1 and c-Myc in K562/G01 cells which circCRKL was knocked down (Additional file 2 : Figure S2E).…”

Section: Resultsmentioning

confidence: 99%

circCRKL, a circRNA derived from CRKL, regulates BCR-ABL via sponging miR-877-5p to promote chronic myeloid leukemia cell proliferation

et al. 2022

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Background The BCR-ABL fusion protein is the key factor that results in the occurrence of chronic myeloid leukemia (CML). Imatinib (IM) is a targeted inhibitor of BCR-ABL to achieve complete remission. However, remission failure occurs due to acquired resistance caused by secondary BCR-ABL mutations, underlining the need for novel BCR-ABL-targeting strategies. Circular RNAs (circRNAs) derived from tumor-related genes have been revealed as possible therapeutic targets for relevant cancers in recent investigations. In CML, the roles of this kind of circRNA are yet obscure. Methods Firstly, RT-qPCR was used for determining circCRKL expression level in cell lines and clinical samples, RNase R and Actinomycin D were employed to verify the stability of circCRKL. Then shRNAs were designed to specifically knockdown circCRKL. The function of circCRKL in vitro was investigated using CCK-8, colony formation assay, and flow cytometry, while a CML mouse model was constructed to explore the function in vivo. Finally, a dual-luciferase reporter assay, RNA pull-down, RNA immunoprecipitation, and rescue experiments were conducted to investigate the mechanism of circCRKL functioning. Results Here, we determined circCRKL, which derives from CML-relevant gene CRKL, is over-expressed in BCR-ABL+ cells. Then we noticed knocking down circCRKL using shRNA lentivirus dampens the proliferation of BCR-ABL+ cells both in vitro and in vivo, and augments susceptibility of resistant cells to IM. Intriguingly, we observed that circCRKL has a considerable impact on the expression level of BCR-ABL. Mechanistically, circCRKL could behave like a decoy for miR-877-5p to enhance the BCR-ABL level, allowing BCR-ABL+ cells to maintain viability. Conclusions Overall, the current study uncovers that circCRKL is specifically expressed and regulates BCR-ABL expression level via decoying miR-877-5p in BCR-ABL+ cells, highlighting that targeting circCRKL along with imatinib treatment could be utilized as a potential therapeutic strategy for CML patients.

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“…Progeny cells from these clones have a strong ability to proliferate and lose the ability to differentiate into relatively mature blood cells. Recent studies showed that the protective upregulation of Wnt/β-catenin and ABC transporter signals induced by imatinib treatment is neutralized by knockdown of transcription factor 7 (TCF7), one of the main Wnt/β-catenin signaling mediators [Zhang et al, 2020]. While uncontrolled cell proliferation that precedes cancer involves several cell clones, the crucial event leading to cancer is the selection and further expansion of a single clone, characterized by a "carcinogenic advantage" [Wright, 2002].…”

Section: The Fight Against Cancer Variability: Cancer Evolution and Drug Resistancementioning

confidence: 99%

Evolutionary Mechanisms of Cancer Suggest Rational Therapeutic Approaches

Balzerano

Paccosi

Proietti-De-Santis

2021

Cytogenet Genome Res

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The goal in personalized therapeutic approaches for cancer medicine is to identify specific mutations with prognostic and therapeutic value in order to tailor the therapy for the single patient. The most powerful obstacle for personalized medicine arises from intratumor heterogeneity and clonal evolution, which can promote drug resistance. In this scenario, new technologies, such as next-generation sequencing, have emerged as a central diagnostic tool to profile cancer (epi)genomic landscapes. Therefore, a better understanding of the biological mechanisms underlying cancer evolution is mandatory and represents the current challenge to accurately predict whether cancer will recur after chemotherapy with the aim to tailor rational therapeutic approaches.

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TCF7 knockdown inhibits the imatinib resistance of chronic myeloid leukemia K562/G01 cells by neutralizing the Wnt/β‑catenin/TCF7/ABC transporter signaling axis

Cited by 9 publications

References 50 publications

TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum

TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum

circCRKL, a circRNA derived from CRKL, regulates BCR-ABL via sponging miR-877-5p to promote chronic myeloid leukemia cell proliferation

Evolutionary Mechanisms of Cancer Suggest Rational Therapeutic Approaches

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