miR-196b-5p Regulates Colorectal Cancer Cell Migration and Metastases through Interaction with HOXB7 and GALNT5

Stiegelbauer, Verena; Vychytilova-Faltejskova, Petra; Karbiener, Michael; Pehserl, Anna Maria; Reicher, Andreas; Resel, Margit; Heitzer, Ellen; Ivan, Cristina; Bullock, Marc D.; Ling, Hui; Deutsch, Alexander; Wulf-Goldenberg, Annika; Adiprasito, Jan Basri; Stoeger, Herbert; Haybaeck, Johannes; Svoboda, Marek; Stotz, Michael; Höefler, Gerald; Slabý, Ondřej; Calin, George A.; Gerger, Armin; Pichler, Martin

doi:10.1158/1078-0432.ccr-17-0023

Cited by 68 publications

(60 citation statements)

References 40 publications

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“…Recent studies in colorectal cancer demonstrated that miR-196b-5p expression promotes migration and growth of metastases (41). Therefore, to determine the biological outcome of miR-196b-5p overexpression in human gastric cancer, we investigated the influences of miR-196b-5p in gastric cancer cell proliferation and invasion.…”

Section: Resultsmentioning

confidence: 99%

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Methylation of the HOXA10 Promoter Directs miR-196b-5p–Dependent Cell Proliferation and Invasion of Gastric Cancer Cells

Shao

Chen

Peng

et al. 2018

Molecular Cancer Research

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The cross-talk between epigenetics and miRNA expression plays an important role in human tumorigenesis. Herein, the regulation and role of miR-196b-5p in gastric cancer was investigated. Quantitative real-time RT-PCR (qPCR) demonstrated that miR-196b-5p is significantly overexpressed in human gastric cancer tissues (P<0.01). In addition, it was determined that HOXA10, a homeobox family member and host gene for miR-196b-5p, is overexpressed and positively correlated with miR-196b-5p expression levels (P<0.001). Quantitative pyrosequencing methylation analysis, demonstrated significantly lower levels of DNA methylation at the HOXA10 promoter in gastric cancer, as compared to non-neoplastic gastric mucosa specimens. 5-Aza-2′-deoxycytidine treatment confirmed that demethylation of HOXA10 promoter induces the expression of HOXA10 and miR-196b-5p in gastric cancer cell model systems. Using the Tff1-KO mouse model of gastric neoplasia, hypo-methylation and overexpression of HOXA10 and miR-196b-5p in gastric tumors was observed, as compared to normal gastric mucosa from Tff1-WT mice. Mechanistically, reconstitution of TFF1 in human gastric cancer cells lead to an increased HOXA10 promoter methylation with reduced expression of HOXA10 and miR-196b-5p. Functionally, miR-196b-5p reconstitution promoted human gastric cancer cell proliferation and invasion in vitro. In summary, the current data demonstrates overexpression of miR-196b-5p in gastric cancer and suggests that TFF1 plays an important role in suppressing the expression of miR-196b-5p by mediating DNA methylation of the HOXA10 promoter. Loss of TFF1 expression may promote proliferation and invasion of gastric cancer cells through induction of promoter hypo-methylation and expression of the HOXA10/miR-196b-5p axis.

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Section: Resultsmentioning

confidence: 99%

“…miR-196b-5p overexpression has been reported in gastrointestinal cancer types, such as pancreatic (47), colorectal (41), and gastric (48). However, the molecular relationship between miR-196b-5p and HOXA10 is not clear.…”

Section: Discussionmentioning

confidence: 99%

Methylation of the HOXA10 Promoter Directs miR-196b-5p–Dependent Cell Proliferation and Invasion of Gastric Cancer Cells

Shao

Chen

Peng

et al. 2018

Molecular Cancer Research

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“…Twenty-four studies demonstrated the downregulation of twenty-five miRs associated with advanced TNM stage: miR-302c 67 , miR-466 68 , miR-340 69 , miR-196b-5p 70 , miR-944 71 , miR-30d 72 , miR-22 50 , miR-296 73 , miR-384 74 , miR-199b 48 , miR-128 75 , miR-33b 76 , miR-155-5p 77 , miR-154 78 , miR-149 79 , miR-194 80 , miR-133b 37 , miR-15a 34 , miR-100 81 , miR-133a 41 , miR-335 82 , miR-378a-3p 58 , miR-378a-5p 58 , miR-218 83 and miR-16 34 . Two studies demonstrated the upregulation of miR-182 43, 44 associated with advanced TNM stage and others 22 studies pointed 23 different upregulated miRs associated with advanced TNM stage.…”

Section: Resultsmentioning

confidence: 99%

“…Among the evaluated studies, 49 demonstrated the downregulation of miR-199b 47, 48 , miR-6852 106 , miR-302c 67 , miR-466 68 , miR-650 123 , miR-196b-5p 70 , miR-944 71 , miR-30d 72 , miR-296 73 , miR-187 124 , let-7a-5p 98 , miR-132 99 , miR-206 100 , miR-148a 125 , miR-33b 76 , miR-99b-5p 120 , miR-154 78 , miR-217 126 , miR-149 79 , miR-194 80 , miR-7 56 , miR-24-3p 54 , miR-29b 127 , miR-15a 34 , miR-16 34, 36 , miR-204-5p 128 , miR-96-5p 121 , miR-193a-5p 108 , miR-100 81 , miR-133a 41 , miR-139-5p 129 , miR-124-5p 130 , miR-335 82 , miR-378 101 , miR-126 40 , miR-378a-3p 58 , miR-378a-5p 58 , miR-218 83 , miR-138 110 , miR-625 111 , miR-212 112 , miR-124 131 , miR-22 49 , miR-133b 39 , miR-193a-3p 104 , miR-195 113 and miR-30c 103 associated with worse prognosis (lower overall survival) of CRC patients. Fifty-six studies identified the upregulation of miR-181a 31–33 , miR-182 43, 44 , miR-1296 84 , miR-888 64 , miR-28-5p 132 , miR-183 45, 46 , miR-200c 114 , miR-34a 133 , miR-15a-5p 134 , miR-181c 135 , miR-24-3p 53 , miR-16 35 , miR-7 55 , miR-96 86 , miR-1260b 115 , miR-20a-5p 63 , miR-517a 87 , miR-503 136 , miR-106b 88 , miR-211 137 , miR-320e 89 , miR-592 90 , miR-196a 57 , miR-196b 57 , miR-376a …”

Section: Resultsmentioning

confidence: 99%

Tissue micro-RNAs associated with colorectal cancer prognosis: a systematic review

Santos

Penna

Carneiro

et al. 2019

Preprint

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Colorectal cancer (CRC) is a multifactorial disease commonly diagnosed worldwide, with high mortality rates. Several studies demonstrate important associations between differential expression of micro-RNAs (miRs) and the prognosis of CRC. However, only a few systematic reviews emphasize the most relevant miRs able to contribute to the establishment of new prognostic biomarkers in CRC patients. The present study aimed to identify differentially expressed tissue miRs associated with prognostic factors in CRC patients, through a systematic review of the Literature. Using the PubMed database, Cochrane Library and Web of Science, studies published in English evaluating miRs differentially expressed in tumor tissue and significantly associated with the prognostic aspects of CRC were selected. All the included studies used RT-PCR (Taqman or SYBR Green) for miR expression analysis and the period of publication was from 2009 to 2018. A total of 115 articles accomplished the inclusion criteria and were included in the review. The studies investigated the expression of 102 different miRs associated with prognostic aspects in colorectal cancer patients. The most frequent oncogenic miRs investigated were miR-21, miR-181a, miR-182, miR-183, miR-210 and miR-224 and the hyperexpression of these miRs was associated with distant metastasis, lymph node metastasis and worse survival in patients with CRC. The most frequent tumor suppressor miRs were miR-126, miR-199b and miR-22 and the hypoexpression of these miRs was associated with distant metastasis, worse prognosis and a higher risk of disease relapse (worse disease-free survival). Specific tissue miRs are shown to be promising prognostic biomarkers in patients with CRC, given their strong association with the prognostic aspects of these tumors, however, new studies are necessary to establish the sensibility and specificity of the miRs in order to use them in clinical practice.

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“…Buprenorphine exposure was associated with significant downregulation of miR-196a and miR-196b. Multiple predicted and/or validated target genes of miR-196a and miR-196b have been associated with developmental disorders (ZMYND11 72 for autism 73,74 and intellectual disability 75 ; HOXB7 76 for Huntington's disease 77 and neural tube defects 78,79 ). Other targets of downregulated miRs in opioid cases also have a role in opioid addiction (AQP4, 80,81 NR2C2 82 ) and co-dependence of alcohol and nicotine (NR2C2 83 ).…”

Section: Moud Associated With Altered Fce Protein Cargo: Pilot Analmentioning

confidence: 99%

Novel biomarkers to assess in utero effects of maternal opioid use: First steps toward understanding short‐ and long‐term neurodevelopmental sequelae

Goetzl

Thompson-Felix

Darbinian

et al. 2019

Genes Brain and Behavior

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Maternal opioid use disorder is common, resulting in significant neonatal morbidity and cost. Currently, it is not possible to predict which opioid‐exposed newborns will require pharmacotherapy for neonatal abstinence syndrome. Further, little is known regarding the effects of maternal opioid use disorder on the developing human brain. We hypothesized that novel methodologies utilizing fetal central nervous system‐derived extracellular vesicles isolated from maternal blood can address these gaps in knowledge. Plasma from opioid users and controls between 9 and 21 weeks was precipitated and extracellular vesicles were isolated. Mu opioid and cannabinoid receptor levels were quantified. Label‐free proteomics studies and unbiased small RNA next generation sequencing was performed in paired fetal brain tissue. Maternal opioid use disorder increased mu opioid receptor protein levels in extracellular vesicles independent of opioid equivalent dose. Moreover, cannabinoid receptor levels in extracellular vesicles were upregulated with opioid exposure indicating cross talk with endocannabinoids. Maternal opioid use disorder was associated with significant changes in extracellular vesicle protein cargo and fetal brain micro RNA expression, especially in male fetuses. Many of the altered cargo molecules and micro RNAs identified are associated with adverse clinical neurodevelopmental outcomes. Our data suggest that assays relying on extracellular vesicles isolated from maternal blood extracellular vesicles may provide information regarding fetal response to opioids in the setting of maternal opioid use disorder. Prospective clinical studies are needed to evaluate the association between extracellular vesicle biomarkers, risk of neonatal abstinence syndrome and neurodevelopmental outcomes.

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miR-196b-5p Regulates Colorectal Cancer Cell Migration and Metastases through Interaction with HOXB7 and GALNT5

Cited by 68 publications

References 40 publications

Methylation of the HOXA10 Promoter Directs miR-196b-5p–Dependent Cell Proliferation and Invasion of Gastric Cancer Cells

Methylation of the HOXA10 Promoter Directs miR-196b-5p–Dependent Cell Proliferation and Invasion of Gastric Cancer Cells

Tissue micro-RNAs associated with colorectal cancer prognosis: a systematic review

Novel biomarkers to assess in utero effects of maternal opioid use: First steps toward understanding short‐ and long‐term neurodevelopmental sequelae

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