HIC1 Silencing in Triple-Negative Breast Cancer Drives Progression through Misregulation of LCN2

Cheng, Guangcun; Sun, Xun; Wang, Jinglong; Xiao, Gang; Wang, Xiuming; Fan, Xuemei; Zu, Lidong; Hao, Mingang; Qu, Qing; Mao, Yan Ping; Xue, Yi; Wang, Jianhua

doi:10.1158/0008-5472.can-13-2420

Cited by 47 publications

(50 citation statements)

References 42 publications

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“…Efficient overexpression of HIC1 in MCF-7 cells was achieved (Supplementary Figures S4A and S4C). In agreement with previous findings, 16, 17 overexpression of HIC1 in MCF-7 cells indeed caused increased cell apoptosis and decreased cell invasion (Figures 3d–g), indicating that HIC1 and miR-23a~27a~24-2 cluster have the opposite effect on cell apoptosis and invasion. More importantly, apoptosis and invasion assays revealed that ectopic expression of miR-23a~27a~24-2–resistant HIC1 dramatically attenuated the inhibitory effect of the miR-23a~27a~24-2 cluster on cell apoptosis and stimulatory effect on cell invasion (Figures 3d–g).…”

Section: Resultssupporting

confidence: 93%

“…15 HIC1, a tumor-suppressor gene that is downregulated in many human cancers, 16 was identified as an ideal candidate. The predicted interactions between miR-23~27~24 clusters and HIC1 3′-UTR are illustrated in Figure 2a.…”

Section: Resultsmentioning

confidence: 99%

“…16, 17 To test whether miR-23a~27a~24-2 may suppress HIC1 expression to affect cell apoptosis and invasion, we transfected MCF-7 cells with both mixture of pre-miR-23a, pre-miR-27a, pre-miR-24 and a plasmid designed to specially express the full-length ORF of HIC1 without the miR-23a~27a~24-2–responsive 3′-UTR. Efficient overexpression of HIC1 in MCF-7 cells was achieved (Supplementary Figures S4A and S4C).…”

Section: Resultsmentioning

confidence: 99%

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HIC1 and miR-23~27~24 clusters form a double-negative feedback loop in breast cancer

Liang

Zhou

et al. 2016

Cell Death Differ

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MicroRNAs (miRNAs) have emerged as a major regulator of the initiation and progression of human cancers, including breast cancer. However, the cooperative effects and transcriptional regulation of multiple miRNAs, especially miRNAs that are present in clusters, remain largely undiscovered. Here we showed that all members of the miR-23~27~24 clusters are upregulated and function as oncogenes in breast cancer and simultaneously target HIC1. Furthermore, we found that HIC1 functions as a transcriptional repressor to negatively control the expression of miR-23~27~24 clusters and forms a double-negative (overall positive) feedback loop. This feedback regulatory pathway is important because overexpression of miR-23~27~24 clusters can remarkably accelerate tumor growth, whereas restoration of HIC1 significantly blocks tumor growth in vivo. A mathematical model was created to quantitatively illustrate the regulatory circuit. Our finding highlights the cooperative effects of miRNAs in a cluster and adds another layer of complexity to the miRNA regulatory network. This study may also provide insight into the molecular mechanisms of breast cancer progression.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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HIC1 and miR-23~27~24 clusters form a double-negative feedback loop in breast cancer

Liang

Zhou

et al. 2016

Cell Death Differ

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“…For example, HIC-1 mRNA and protein levels were reported to be low or absent in pancreatic ductal adenocarcinoma (PDAC) tissues, and its expression gradually decreased during the progression of PDAC; negative HIC-1 expression predicted advanced pathological stage and poor patient survival [25]. Moreover, HIC-1 expression was found to be silenced in triple-negative breast cancer [24]. Although studies have identified HIC-1 as having frequent changes in hypermethylation or loss of heterozygosity in many human cancers [40, 41], the molecular mechanisms through which HIC-1 inhibits cancer progression remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…Bioinformatics analysis of miR - 4532 has shown that hypomethylated in cancer-1 (HIC-1) may be an miRNA target gene involved in the regulation of resistance of cancer cells to chemotherapeutic drugs. The HIC - 1 gene, located on chromosome 17p13.3, is a tumor-suppressor gene that is frequently silenced or deleted in a variety of human cancers, such as leukemia, liver cancer, pancreatic cancer, and breast cancer [21–24]. HIC-1 is involved in several complex biological functions in the regulation of drug resistance in cancer, including cell survival, cell growth, cell motility, and cell migration [25].…”

Section: Introductionmentioning

confidence: 99%

Downregulation of hypermethylated in cancer-1 by miR-4532 promotes adriamycin resistance in breast cancer cells

et al. 2018

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BackgroundMicroRNAs are small RNAs (~ 22 nt) that modulate the expression of thousands of genes in tumors and play important roles in the formation of multidrug resistance. In this study, we firstly investigated that miR-4532 involved in the multidrug resistance formation of breast cancer by targeting hypermethylated in cancer 1 (HIC-1), a tumor-suppressor gene.MethodsTo identify and characterize the possible miRNAs in regulating multidrug resistance, we employed the transcriptome sequencing approach to profile the changes in the expression of miRNAs and their target mRNAs were obtained by bioinformatics prediction. Then the molecular biology experiments were conducted to confirm miR-4532 involved in multidrug resistance formation of breast cancer.ResultsThe luciferase reporter assay experiment was employed to confirm that HIC-1 was the target of miR-4532. Transfection with an miR-4532 mimic indicated miR-4532 mimic significantly increased breast cancer cell resistance to adriamycin. Cell proliferation and invasion assay experiments showed overexpression of HIC-1 inhibited the invasion and metastasis of breast cancer cells. Meanwhile, the interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway was confirmed to be involving in multidrug resistance by western blotting experiments.ConclusionsThese results suggest that downregulation of hypermethylated in cancer-1 by miR-4532 could promote adriamycin resistance in breast cancer cells, in which the IL-6/STAT3 pathway was regulated by the HIC-1. This finding might contribute to new therapeutic target for reversal of tumor resistance.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0616-x) contains supplementary material, which is available to authorized users.

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Hypermethylated in cancer 1 (HIC1) suppresses bladder cancer progression by targeting yes‐associated protein (YAP) pathway

Zhou

Zhang

Han

et al. 2018

J of Cellular Biochemistry

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Objectives Bladder cancer (BCa) is the most common malignant tumor in the urinary system. Growing evidence suggests that as a tumor suppressor gene, hypermethylated in cancer 1 (HIC1) is correlated with various malignancies in the modulation of tumor progression. This study aims to investigate the effect of HIC1 on regulating the proliferation, migration, and invasion of BCa. Methods Quantitative reverse transcription polymerase chain reaction (qRT‐PCR) and Western blot (WB) were used to evaluate the expression of HIC1 messenger RNA and protein in human BCa tissues and cells. Proliferation, migration and invasion assays, and flow cytometry assay were performed to assess the biological functional role of HIC1 in BCa. Co‐immunoprecipitation (Co‐IP) examined the protein‐protein interaction. The signaling pathways involved in the mode of action of HIC1 in BCa were also investigated. Results HIC1 was found downregulated in tested samples. Cloning formation assay and cell‐proliferation activity analysis showed that overexpression of HIC1 significantly inhibited the proliferation of BCa cells, while knockdown led to the opposite, namely the promotion of the proliferation. Flow cytometry assay confirmed the arrest of the cell cycle at the G1 phase with overexpression of HIC1 observed. Moreover, HIC1 inhibited migration and invasion of BCa. Co‐IP showed the binding between YAP (yes‐associated protein) and TEAD (TEA domain/transcription enhancer factor family members) as well as the cancerostatic activity of HIC1, partially manifested via its negative regulation of YAP signaling pathway. Conclusions Our data unprecedently showed that HIC1 was responsible for the inhibition of proliferation, migration, and invasion of BCa via the YAP signaling pathway. These findings suggested that therapeutic strategies regulating HIC1 expression might provide effective treatments for BCa.

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HIC1 Silencing in Triple-Negative Breast Cancer Drives Progression through Misregulation of LCN2

Cited by 47 publications

References 42 publications

HIC1 and miR-23~27~24 clusters form a double-negative feedback loop in breast cancer

HIC1 and miR-23~27~24 clusters form a double-negative feedback loop in breast cancer

Downregulation of hypermethylated in cancer-1 by miR-4532 promotes adriamycin resistance in breast cancer cells

Hypermethylated in cancer 1 (HIC1) suppresses bladder cancer progression by targeting yes‐associated protein (YAP) pathway

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