ChrXq27.3 miRNA cluster functions in cancer development

AbstractMicroRNAs (miRNAs) regulate the expression of their target genes post-transcriptionally; thus, they are deeply involved in fundamental biological processes. miRNA clusters contain two or more miRNA-encoding genes, and these miRNAs are usually coexpressed due to common expression mechanisms. Therefore, miRNA clusters are effective modulators of biological pathways by the members coordinately regulating their multiple target genes, and an miRNA cluster located on the X chromosome q27.3 region has received much attention in cancer research recently. In this review, we discuss the novel findings of the chrXq27.3 miRNA cluster in various types of cancer.The chrXq27.3 miRNA cluster contains 30 mature miRNAs synthesized from 22 miRNA-encoding genes in an ~ 1.3-Mb region. The expressions of these miRNAs are usually negligible in many normal tissues, with the male reproductive system being an exception. In cancer tissues, each miRNA is dysregulated, compared with in adjacent normal tissues. The miRNA-encoding genes are not uniformly distributed in the region, and they are further divided into two groups (the miR-506-514 and miR-888-892 groups) according to their location on the genome. Most of the miRNAs in the former group are tumor-suppressive miRNAs that are further downregulated in various cancers compared with normal tissues. miR-506-3p in particular is the most well-known miRNA in this cluster, and it has various tumor-suppressive functions associated with the epithelial–mesenchymal transition, proliferation, and drug resistance. Moreover, other miRNAs, such as miR-508-3p and miR-509-3p, have similar tumor-suppressive effects. Hence, the expression of these miRNAs is clinically favorable as prognostic factors in various cancers. However, the functions of the latter group are less understood. In the latter group, miR-888-5p displays oncogenic functions, whereas miR-892b is tumor suppressive. Therefore, the functions of the miR-888–892 group are considered to be cell type- or tissue-specific.In conclusion, the chrXq27.3 miRNA cluster is a critical regulator of cancer progression, and the miRNAs themselves, their regulatory mechanisms, and their target genes might be promising therapeutic targets.

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miR551b Regulates Colorectal Cancer Progression by Targeting the ZEB1 Signaling Axis

Cancers ◽

10.3390/cancers11050735 ◽

2019 ◽

Vol 11 (5) ◽

pp. 735 ◽

Cited By ~ 2

Author(s):

Kwang Seock Kim ◽

Dongjun Jeong ◽

Ita Novita Sari ◽

Yoseph Toni Wijaya ◽

Nayoung Jun ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Lines ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Ectopic Expression ◽

Xenograft Model ◽

Mesenchymal Transition ◽

Normal Tissues

Our current understanding of the role of microRNA 551b (miR551b) in the progression of colorectal cancer (CRC) remains limited. Here, studies using both ectopic expression of miR551b and miR551b mimics revealed that miR551b exerts a tumor suppressive effect in CRC cells. Specifically, miR551b was significantly downregulated in both patient-derived CRC tissues and CRC cell lines compared to normal tissues and non-cancer cell lines. Also, miR551b significantly inhibited the motility of CRC cells in vitro, including migration, invasion, and wound healing rates, but did not affect cell proliferation. Mechanistically, miR551b targets and inhibits the expression of ZEB1 (Zinc finger E-box-binding homeobox 1), resulting in the dysregulation of EMT (epithelial-mesenchymal transition) signatures. More importantly, miR551b overexpression was found to reduce the tumor size in a xenograft model of CRC cells in vivo. Furthermore, bioinformatic analyses showed that miR551b expression levels were markedly downregulated in the advanced-stage CRC tissues compared to normal tissues, and ZEB1 was associated with the disease progression in CRC patients. Our findings indicated that miR551b could serve as a potential diagnostic biomarker and could be utilized to improve the therapeutic outcomes of CRC patients.

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TRIM50 Suppresses Pancreatic Cancer Progression and Reverses the Epithelial-Mesenchymal Transition via Facilitating the Ubiquitous Degradation of Snail1

Frontiers in Oncology ◽

10.3389/fonc.2021.695740 ◽

2021 ◽

Vol 11 ◽

Author(s):

Rongkun Li ◽

Lili Zhu ◽

Yangxizi Peng ◽

Xiaoxin Zhang ◽

Chunhua Dai ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Tumor Development ◽

Poor Survival ◽

Mesenchymal Transition ◽

Functional Roles ◽

Pancreatic Cancer Cells ◽

Tripartite Motif ◽

Cancer Tissues

Emerging evidence suggests that the tripartite motif (TRIM) family play important roles in tumor development and progression. Tripartite motif-containing 50 (TRIM50) is a member of the TRIM family, but little is known regarding its expression and potential functional roles in cancer. In this study, we first analyzed the expression pattern and clinical significance of TRIM50 in pancreatic cancer and found that TRIM50 expression is significantly reduced in pancreatic cancer tissues and its downregulation is associated with poor survival for pancreatic cancer patients. Functionally, TRIM50 overexpression in pancreatic cancer cells decreases their proliferation and motility capabilities and reverses the epithelial-mesenchymal transition (EMT) process, whereas TRIM50 depletion had the opposite effects. Mechanically, TRIM50 directly interacts with Snail1, a key regulator of EMT, and acts as an E3 ubiquitin ligase to target Snail1 for ubiquitous degradation. The function of TRIM50 in suppressing cell migration and EMT depends on TRIM50-promoted Snail1 degradation. In conclusion, our findings identify TRIM50 as a tumor suppressor that inhibits pancreatic cancer progression and reverses EMT via degrading Snail1 and provide new insights into the progression of pancreatic cancer.

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Golgi Phosphoprotein 73: The Driver of Epithelial-Mesenchymal Transition in Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.783860 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yiming Liu ◽

Xinyang Hu ◽

Shiyao Liu ◽

Sining Zhou ◽

Zhi Chen ◽

...

Keyword(s):

Cancer Progression ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Secretory Protein ◽

Multifunctional Protein ◽

Mesenchymal Transition ◽

Functional Roles ◽

Research Fields ◽

Cancer Tissues ◽

Related Proteins

Golgi phosphoprotein 73 (GP73, also termed as GOLM1 or GOLPH2) is a glycosylated protein residing on cis-Golgi cisternae and highly expressed in various types of cancer tissues. Since GP73 is a secretory protein and detectable in serum derived from cancer patients, it has been regarded as a novel serum biomarker for the diagnosis of different cancers, especially hepatocellular carcinoma (HCC). However, the functional roles of GP73 in cancer development are still poorly understood. In recent years, it has been discovered that GP73 acts as a multifunctional protein-facilitating cancer progression, and strikingly, it has been identified as a leading factor promoting epithelial-mesenchymal transition (EMT) of cancer cells and causing cancer metastasis. In this review, we have overviewed the latest findings of the functional roles of GP73 in elevating cancer progression, especially in facilitating EMT and cancer metastasis through modulating expression, transactivation, and trafficking of EMT-related proteins. In addition, unsolved research fields of GP73 have been lightened, which might be helpful to elucidate the regulatory mechanisms of GP73 on EMT and provide potential approaches in therapeutics against cancer metastasis.

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The YAP1–NMU Axis Is Associated with Pancreatic Cancer Progression and Poor Outcome: Identification of a Novel Diagnostic Biomarker and Therapeutic Target

Cancers ◽

10.3390/cancers11101477 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1477 ◽

Cited By ~ 4

Author(s):

Yoo ◽

Lee ◽

Jun ◽

Noh ◽

Lee ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Target Genes ◽

Epithelial Mesenchymal Transition ◽

The Cancer Genome Atlas ◽

Mesenchymal Transition ◽

Tumor Group ◽

Cancer Genome Atlas

Yes-associated protein (YAP)-1 is highly upregulated in pancreatic cancer and associated with tumor progression. However, little is known about the role of YAP1 and related genes in pancreatic cancer. Here, we identified target genes regulated by YAP1 and explored their role in pancreatic cancer progression and the related clinical implications. Analysis of different pancreatic cancer databases showed that Neuromedin U (NMU) expression was positively correlated with YAP1 expression in the tumor group. The Cancer Genome Atlas data indicated that high YAP1 and NMU expression levels were associated with poor mean and overall survival. YAP1 overexpression induced NMU expression and transcription and promoted cell motility in vitro and tumor metastasis in vivo via upregulation of epithelial–mesenchymal transition (EMT), whereas specific inhibition of NMU in cells stably expressing YAP1 had the opposite effect in vitro and in vivo. To define this functional association, we identified a transcriptional enhanced associate domain (TEAD) binding site in the NMU promoter and demonstrated that YAP1–TEAD binding upstream of the NMU gene regulated its transcription. These results indicate that the identified positive correlation between YAP1 and NMU is a potential novel drug target and biomarker in metastatic pancreatic cancer.

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PKM2 Promotes Breast Cancer Progression by Regulating Epithelial Mesenchymal Transition

Analytical Cellular Pathology ◽

10.1155/2020/8396023 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Hui Xiao ◽

Longxiao Zhang ◽

Yuan Chen ◽

Chengjun Zhou ◽

Xiao Wang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Tumor Metastasis ◽

Epithelial Mesenchymal Transition ◽

Underlying Mechanism ◽

Mesenchymal Transition ◽

Breast Cancer Metastases ◽

Cancer Metastases ◽

Glucose Intake ◽

Cancer Tissues

Breast cancer is the leading cause of females characterized by high invasive potential. It is necessary to explore the underlying mechanism of breast cancer metastases and to find specific therapeutic targets. PKM2 is considered a new biomarker of cancer with upregulated expression in tumor tissue. PKM2 participates in the cancer-specific Warburg effect to regulate fast glucose intake consumption. Besides, PKM2 also contributes to cancer progression, especially tumor metastasis. In this study, we showed that PKM2 is upregulated in breast cancer tissues and the upregulating of PKM2 in breast cancer correlates with poor prognosis. PKM2 can regulate tumor progression by promoting tumor cell viability and mobility. Furthermore, overexpression of PKM2 can promote EMT to encourage tumor metastasis. These findings indicate PKM2 is a potentially useful diagnostic biomarker and therapeutic target in breast cancer.

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MicroRNA-638 inhibits the progression of breast cancer through targeting HOXA9 and suppressing Wnt/β-cadherin pathway

World Journal of Surgical Oncology ◽

10.1186/s12957-021-02363-7 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Qian Xu ◽

Qianqian Zhang ◽

Mengli Dong ◽

Yuan Yu

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Malignant Tumors ◽

Cell Counting ◽

Luciferase Assay ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Homeobox Protein ◽

Cancer Tissues

Abstract Background Previous studies had shown that microRNA-638 (miR-638) exhibited different effects in malignant tumors. Moreover, the function of miR-638 has not been reported in breast cancer. Hence, we designed this research to explore the function of miR-638 in breast cancer. Methods Firstly, miR-638 expressions were measured in breast cancer tissues via RT-qPCR. Protein expressions were detected through immunocytochemical (IHC) assay and western blot analysis. Then, Cell Counting Kit-8 (CCK-8) assay and Transwell assay were conducted to observe proliferation and motility of the cells. Dual luciferase assay was performed to confirm the binding site between miR-638 and Homeobox protein Hox-A9 (HOXA9). Results Reduced expression of miR-638 was detected in breast cancer. And low miR-638 expression was related to poor prognosis in patients with breast cancer. Functionally, the viability, migration, and invasion of the breast cancer cells were suppressed by miR-638 overexpression. Furthermore, miR-638 can directly bind to HOXA9, and increased expression of HOXA9 was also detected in breast cancer. In particular, HOXA9 upregulation can impair anti-tumor effect of miR-638 in breast cancer, and miR-638 can hinder the Wnt/β-cadherin pathway and epithelial-mesenchymal transition (EMT) in breast cancer. Conclusion miR-638 inhibits breast cancer progression through binding to HOXA9.

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The Aryl Hydrocarbon Receptor Is Expressed in Thyroid Carcinoma and Appears to Mediate Epithelial-Mesenchymal-Transition

Cancers ◽

10.3390/cancers12010145 ◽

2020 ◽

Vol 12 (1) ◽

pp. 145 ◽

Cited By ~ 5

Author(s):

Sonia Moretti ◽

Nicole Nucci ◽

Elisa Menicali ◽

Silvia Morelli ◽

Vittorio Bini ◽

...

Keyword(s):

Thyroid Cancer ◽

Cell Motility ◽

Aryl Hydrocarbon Receptor ◽

Cancer Progression ◽

Target Genes ◽

Epithelial Mesenchymal Transition ◽

Receptor Activation ◽

Mesenchymal Transition ◽

Aryl Hydrocarbon ◽

And Migration

Aryl hydrocarbon receptor (AhR) is expected to promote initiation, progression and invasion of cancer cells regulating proliferation, differentiation, gene expression, inflammation, cell motility and migration. Furthermore, an immunosuppressant function of AhR has been recognized. This study evaluated AhR expression and its role in thyroid cancer progression. AhR expression was assessed by qPCR in 107 thyroid cancer samples (90 PTCs, 11 MTCs, 6 ATCs), and by immunohistochemistry in 41 PTCs. To estimate receptor activation, the expression of target genes CYP1A1 and CYP1B1 was measured. AhR functional effects were evaluated in kynurenine-stimulated FTC-133 and BcPap cell lines by analyzing the expression of genes involved in EMT and cell motility. AhR mRNA expression resulted significantly higher in all the analyzed thyroid cancer samples compared to normal thyroid and a statistically significant correlation with CYP1B1 was detected. Kynurenine-stimulated FTC-133 and BcPap showed the activation of a specific AhR-driven EMT program characterized by E-cadherin decrease and SLUG, N-cadherin and fibronectin increase, resulting in boost of cell motility and invasion. This study confirmed the importance of the IDO1-Kyn-AhR pathway in thyroid cancer tumorigenesis, suggesting an AhR pivotal role in mediating an immunosuppressive microenvironment and favoring the acquisition of a mesenchymal phenotype that could promote invasiveness and metastasis.

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Water-Pipe Smoking Exposure Deregulates a Set of Genes Associated with Human Head and Neck Cancer Development and Prognosis

Toxics ◽

10.3390/toxics8030073 ◽

2020 ◽

Vol 8 (3) ◽

pp. 73

Author(s):

Vanessa M. López-Ozuna ◽

Ishita Gupta ◽

Ryan Liu Chen Kiow ◽

Emad Matanes ◽

Hadeel Kheraldine ◽

...

Keyword(s):

Head And Neck ◽

Cancer Patients ◽

Cancer Progression ◽

Target Genes ◽

Epithelial Mesenchymal Transition ◽

Pcr Analysis ◽

Water Pipe ◽

Mesenchymal Transition ◽

Qrt Pcr ◽

The Impact

Water-pipe smoking (WPS) is becoming the most popular form of tobacco use among the youth, especially in the Middle East, replacing cigarettes rapidly and becoming a major risk of tobacco addiction worldwide. Smoke from WPS contains similar toxins as those present in cigarette smoke and is linked directly with different types of cancers including lung and head and neck (HN) carcinomas. However, the underlying molecular pathways and/or target genes responsible for the carcinogenic process are still unknown. In this study, human normal oral epithelial (HNOE) cells, NanoString PanCancer Pathways panel of 770 gene transcripts and quantitative real-time polymerase chain reaction (qRT-PCR) analysis were applied to discover differentially expressed genes (DEG) modulated by WPS. In silico analysis was performed to analyze the impact of these genes in HN cancer patient’s biology and outcome. We found that WPS can induce the epithelial–mesenchymal transition (EMT: hallmark of cancer progression) of HNOE cells. More significantly, our analysis of NanoString revealed 23 genes deregulated under the effect of WPS, responsible for the modulation of cell cycle, proliferation, migration/invasion, apoptosis, signal transduction, and inflammatory response. Further analysis was performed using qRT-PCR of HNOE WPS-exposed and unexposed cells supported the reliability of our NanoString data. Moreover, we demonstrate those DEG to be upregulated in cancer compared with normal tissue. Using the Kaplan–Meier analysis, we observed a significant association between WPS-deregulated genes and relapse-free survival/overall survival in HN cancer patients. Our findings imply that WPS can modulate EMT as well as a set of genes that are directly involved in human HN carcinogenesis, thereby affecting HN cancer patients’ survival.

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Dual histone reader ZMYND8 inhibits cancer cell invasion by positively regulating epithelial genes

Biochemical Journal ◽

10.1042/bcj20170223 ◽

2017 ◽

Vol 474 (11) ◽

pp. 1919-1934 ◽

Cited By ~ 8

Author(s):

Moitri Basu ◽

Isha Sengupta ◽

Md Wasim Khan ◽

Dushyant Kumar Srivastava ◽

Partha Chakrabarti ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Brdu Incorporation ◽

Proliferation Markers ◽

Mesenchymal Transition ◽

Selective Enrichment ◽

Epithelial Phenotype ◽

Cancer Tissues

Enhanced migratory potential and invasiveness of cancer cells contribute crucially to cancer progression. These phenotypes are achieved by precise alteration of invasion-associated genes through local epigenetic modifications which are recognized by a class of proteins termed a chromatin reader. ZMYND8 [zinc finger MYND (myeloid, Nervy and DEAF-1)-type containing 8], a key component of the transcription regulatory network, has recently been shown to be a novel reader of H3.1K36Me2/H4K16Ac marks. Through differential gene expression analysis upon silencing this chromatin reader, we identified a subset of genes involved in cell proliferation and invasion/migration regulated by ZMYND8. Detailed analysis uncovered its antiproliferative activity through BrdU incorporation, alteration in the expression of proliferation markers, and cell cycle regulating genes and cell viability assays. In addition, performing wound healing and invasion/migration assays, its anti-invasive nature is evident. Interestingly, epithelial–mesenchymal transition (EMT), a key mechanism of cellular invasion, is regulated by ZMYND8 where we identified its selective enrichment on promoters of CLDN1/CDH1 genes, rich in H3K36Me2/H4K16Ac marks, leading to their up-regulation. Thus, the presence of ZMYND8 could be implicated in maintaining the epithelial phenotype of cells. Furthermore, syngeneic mice, injected with ZMYND8-overexpressed invasive breast cancer cells, showed reduction in tumor volume and weight. In concert with this, we observed a significant down-regulation of ZMYND8 in invasive ductal and lobular breast cancer tissues compared with normal tissue. Taken together, our study elucidates a novel function of ZMYND8 in regulating EMT and invasion of cancer cells, possibly through its chromatin reader function.

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Snail and Sonic Hedgehog activation in neuroendocrine tumors of the ileum

Endocrine Related Cancer ◽

10.1677/erc-07-0108 ◽

2007 ◽

Vol 14 (3) ◽

pp. 865-874 ◽

Cited By ~ 41

Author(s):

Volker Fendrich ◽

Jens Waldmann ◽

Farzad Esni ◽

Annette Ramaswamy ◽

Michael Mullendore ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Sonic Hedgehog ◽

Target Genes ◽

Epithelial Mesenchymal Transition ◽

Dependent Manner ◽

Mesenchymal Transition ◽

Epithelial Cancers ◽

Normal Tissues ◽

E Cadherin

The transcription factor Snail represses E-cadherin and induces epithelial–mesenchymal transition, a process also exploited by invasive cancer cells. Aberrant Hedgehog (Hh) signaling was recently observed in a variety of epithelial cancers and it has been shown that the Hh target gene Gli1 induces expression of Snail. In this study, we examined whether Snail and Sonic Hedgehog (SHH) are expressed in neuroendocrine tumors (NETs) of the ileum. Using immunohistochemistry, we found expression of Snail in 22 out of 37 (59%) of evaluated NET samples, but not in adjacent normal tissues. Snail expression was mostly restricted to the invasive front of the tumors. Six of seven liver metastases analyzed were positive for Snail. Intratumoral expression of SHH was detected in 27 out of 37 (73%) tumors. As opposed to Snail, cells expressing SHH were found to be distributed more randomly throughout the tumors. Out of 30 primary NETs, 16 (53%) showed both Snail and SHH expression. Furthermore, we found downregulation of E-cadherin in Snail-expressing cells by immunofluorescence. Real-time RT-PCR revealed conservation of the Hh target genes Gli1, Gli2, and Ptch in the pancreatic carcinoid cell line BON-1, which were downregulated upon Hh inhibition with cyclopamine. Moreover, Hh inhibition attenuated in vitro cell growth in a dose-dependent manner. In conclusion, we describe for the first time that Snail and SHH are overexpressed in a large subset of NETs of the ileum. Aberrant activation of these pathways might be involved in invasion and metastatic spread in NETs.

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