KLF4 overcomes tamoxifen resistance by suppressing MAPK signaling pathway and predicts good prognosis in breast cancer

Jia, Yunlu; Zhou, Jichun; Luo, Xiao; Chen, Miao; Chen, Yongxia; Ji, Wang; Xiong, Hanchu; Ying, Xiaoguo; Hu, Wenxian; Zhao, Wenqiang; Deng, Wuguo; Wang, Linbo

doi:10.1016/j.cellsig.2017.09.025

Cited by 47 publications

(40 citation statements)

References 47 publications

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“…For example, KLF4 has been shown to function as a tumor suppressor in LC 37 , lymphoma, cervical cancer 53 , neuroblastoma, pancreatic ductal gastric cancer, and hepatocellular carcinoma 54 – 57 . In breast cancer, the function of KLF4 is controversial, with reports showing both oncogenic and tumor-suppressive roles 58 – 61 . In addition, acting as a transcription activator or a repressor, KLF4 exerted its activation or inhibitory function after binding different target gene promoters 62 , 63 .…”

Section: Discussionmentioning

confidence: 99%

The novel KLF4/PLAC8 signaling pathway regulates lung cancer growth

et al. 2018

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Accumulating evidence suggests that placenta-specific 8 (PLAC8) plays an important role in normal cellular process and human diseases, including multiple types of human tumors, and its role is highly relied upon in cellular and physiologic contexts. However, there are no reports on its expression profile and biological roles during lung cancer development. In the current study, both the clinical implications and biological effects of PLAC8 in lung cancer (LC) progression were investigated, and we identified and described the novel Krüppel-like factor 4 (KLF4)/PLAC8 regulatory pathway in cancer progression. Elevated PLAC8 levels were positively correlated with tumor size, histological grade, and tumor node metasis (TNM) stage, and LC patients with high PLAC8 expression suffered poor outcomes. In vitro and in vivo assays further revealed that endogenous PLAC8 promoted cell proliferation and tumor formation. We also found downregulated PLAC8 protein in several LC cell lines following the induction of KLF4, and immunohistochemistry analysis of LC tissues by microarray indicated a potential inverse correlation between PLAC8 and KLF4 expression. Luciferase reporter analysis and chromatin immunoprecipitation assays determined that KLF4 negatively regulated PLAC8 promoter activity via directly binding to the promoter region. Furthermore, the growth inhibition resulting from KLF4 overexpression was partially rescued by ectopic PLAC8 expression. Together, our data uncovered a previously unidentified role of PLAC8 as a central mediator in LC progression. PLAC8 was transcriptionally repressed by KLF4, and the novel KLF4/PLAC8 axis may act as a promising candidate target for LC diagnosis and therapy.

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Section: Discussionmentioning

confidence: 99%

The novel KLF4/PLAC8 signaling pathway regulates lung cancer growth

et al. 2018

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“…ADM remains to be one of the most active and widely used chemotherapy agents in the treatment of early and advanced breast cancer. However, drug resistance has limited the effectiveness of the agent in cancer treatment [21,22]. The exact mechanisms behind the resistance are still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

PLAC8 promotes adriamycin resistance via blocking autophagy in breast cancer

chen¹,

Jia

Mao

et al. 2020

Preprint

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Background Adriamycin (ADM) is currently one of the most effective chemotherapeutic agents in breast cancer treatment. However, growing resistance to ADM can lead to treatment failure and poor outcome. The underlying molecular mechanisms in ADM resistance in breast cancer remains unclear. PLAC8 is reported as a novel highly-conserved protein and functions as an oncogene or tumor suppressor in various tumors. Methods Here, we analyzed the expression profile of PLAC8 in breast cancer tissues and breast cancer cell lines, and explored the correlation of PLAC8 expression levels with patients’ outcomes and ADM response. One ADM resistant MCF-7 breast cancer cell (MCF-7/ADM) and its parental cell was used as in vitro models to identify the underlying mechanism of PLAC8 and ADM resistance. Breast cancer cells were transfected with PLAC8 knockdown and overexpression vectors, and MTT and colony formation assays were performed to test the cell response to ADM. Then, we tested the effect of PLAC8 on autophagy pathway by flow cytometry and immunofluorescence analysis, and the change of main autophagy-correlated factors expressions: LC3 and p62. Next, combining treatment of autophagy inhibitor/inducer and PLAC8 downregulation/upregulation revealed the participation of PLAC8 in autophagy pathway to synergistically regulate ADM resistance in breast cancer. Results Here, higher PLAC8 expression was correlated with poorer outcome and aggressive phenotype in breast cancer, and breast cancer patients with higher PLAC8 expression showed potential ADM resistance. PLAC8 expression level was also significantly elevated in ADM resistant MCF-7 breast cancer cells (MCF-7/ADM), compared to parental MCF-7 cells. In vitro experiments further confirmed that PLAC8 inhibition by siRNA or enforced overexpression by infecting pcDNA3.1(C)-PLAC8 plasmid correspondingly decreased or increased the ADM resistance. Subsequently, we demonstrated that ectopic PLAC8 expression in MCF-7/ADM cell blocked the accumulation of the autophagy-associated protein LC3II, and resulted in cellular accumulation of p62. Rapamycin-triggered autophagy significantly increased cell response to ADM, while the autophagy inhibitor 3-MA enhanced ADM resistance. Actually, 3-MA and PLAC8 could synergistically enhance ADM resistance via blocking the autophagy process. Additionally, the downregulation of p62 by siRNA attenuated the activation of autophagy and PLAC8 expression in breast cancer cells. Conclusion Our findings suggest that PLAC8, through participation of p62, inhibits autophagy and consequently results in ADM resistance in breast cancer. PLAC8/p62/autophagy pathway may act as novel therapeutic targets in breast cancer treatment and has potential clinical application in overcoming ADM resistance.

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“…MAPK signaling pathway is a critical key regulator in cellular functions, like cell differentiation, proliferation, differentiation, survival and apoptosis. The higher MAPK expression in subtypes of BC leads to invasive phenotypes and poor prognosis [29][30][31]. Hedgehog signaling pathway is another signaling pathways that constitutively dysregulated in BC cells.…”

Section: Discussionmentioning

confidence: 99%

The Expression of miR-513c and miR-3163 was Downregulated in Tumor Tissues Compared with Margin Tissues of Patients With Breast Cancer

Delgir

Ilkhani

Safi

et al. 2020

Preprint

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Background Breast cancer (BC) is the most common invasive cancer with different subtypes that its metabolism is unique compared with normal cells. Glutamine is considered a critical nutrition for tumor cell growth and therefore, targeting glutamine metabolism, especially Glutaminase, which catalyzed the conversion of glutamine to glutamate can be beneficial to design anti-cancer agents. Recently, evidence has shown that miRNAs with short length and single strand properties play a significant role in regulating the genes related to glutamine metabolism and may control the development of cancer.Methods Since, in-silico analysis confirmed that miR-513c and miR-3163 might be involved in glutamine metabolism, the expression level of these two miRNAs was evaluated in eighty BC tissues and margin tissues. The data were analyzed to evaluate the correlation between expression level of these miRNAs and patient’s characteristics such as abortion history, family history, and age. Furthermore, in-silico analysis was applied to predict the potential biological processes and molecular pathways of miR-513c and miR-3163 based on its gene targets.Results In-silico studies revealed the top categories of biological processes and pathways that play a critical role in cancer development were target genes for miR-513c and miR-3163. The current study showed that miR-513c (P-value = 0.02062 and fold change= -2.3801) and miR-3163 (P-value = 0.02034 and fold change= -2.3792) were downregulated in tumor tissues compared to margin tissues. Furthermore, the subgroup studies did not show any substantial relationship between expression levels of these two miRNAs and factors such as age, family history cancer, and abortion.Conclusion Based on our data, miR-513c and miR-3163 may be offered as a potential diagnosis and therapeutic targets for patients with BC.

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KLF4 overcomes tamoxifen resistance by suppressing MAPK signaling pathway and predicts good prognosis in breast cancer

Cited by 47 publications

References 47 publications

The novel KLF4/PLAC8 signaling pathway regulates lung cancer growth

The novel KLF4/PLAC8 signaling pathway regulates lung cancer growth

PLAC8 promotes adriamycin resistance via blocking autophagy in breast cancer

The Expression of miR-513c and miR-3163 was Downregulated in Tumor Tissues Compared with Margin Tissues of Patients With Breast Cancer

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