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miR-126-3p Inhibits Thyroid Cancer Cell Growth and Metastasis, and Is Associated with Aggressive Thyroid Cancer.

Xiong Y, Kotian S, Zeiger MA, Zhang L, Kebebew E - PLoS ONE (2015)

Bottom Line: We found that miR-126-3p expression was significantly lower in larger tumors, in tumor samples with extrathyroidal invasion, and in higher risk group thyroid cancer in 496 papillary thyroid cancer samples from The Cancer Genome Atlas study cohort.In an independent sample set, lower miR-126-3p expression was observed in follicular thyroid cancers (which have capsular and angioinvasion) as compared to follicular adenomas.Of these 14 genes, SLC7A5 and ADAM9 were confirmed to be inhibited by miR-126-3p overexpression and to be direct targets of miR-136-3p.

View Article: PubMed Central - PubMed

Affiliation: Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.

ABSTRACT

Background: Previous studies have shown that microRNAs are dysregulated in thyroid cancer and play important roles in the post-transcriptional regulation of target oncogenes and/or tumor suppressor genes.

Methodology/principal findings: We studied the function of miR-126-3p in thyroid cancer cells, and as a marker of disease aggressiveness. We found that miR-126-3p expression was significantly lower in larger tumors, in tumor samples with extrathyroidal invasion, and in higher risk group thyroid cancer in 496 papillary thyroid cancer samples from The Cancer Genome Atlas study cohort. In an independent sample set, lower miR-126-3p expression was observed in follicular thyroid cancers (which have capsular and angioinvasion) as compared to follicular adenomas. Mechanistically, ectopic overexpression of miR-126-3p significantly inhibited thyroid cancer cell proliferation, in vitro (p<0.01) and in vivo (p<0.01), colony formation (p<0.01), tumor spheroid formation (p<0.05), cellular migration (p<0.05), VEGF secretion and endothelial tube formation, and lung metastasis in vivo. We found 14 predicted target genes, which were significantly altered upon miR-126-3p transfection in thyroid cancer cells, and which are involved in cancer biology. Of these 14 genes, SLC7A5 and ADAM9 were confirmed to be inhibited by miR-126-3p overexpression and to be direct targets of miR-136-3p.

Conclusions/significance: To our knowledge, this is the first study to demonstrate that miR-126-3p has a tumor-suppressive function in thyroid cancer cells, and is associated with aggressive disease phenotype.

No MeSH data available.


Related in: MedlinePlus

Lower miR-126-3p expression is associated with aggressive thyroid cancer.(A) miR-126-3p is significantly lower in larger papillary thyroid cancer (T3 compared to T2 and T1 tumors). Data for TCGA samples with available tumor size data. T1 tumors less than 2cm and not growing outside the thyroid, T2 tumors > 2cm but < 4cm and not growing outside the thyroid, T3 tumors measuring > 4cm or growing outside the thyroid. ** indicates p < 0.01, *** indicates p < 0.001. Y axis is log10 normalized expression. (B) miR-126-3p expression is significantly lower in papillary thyroid cancer with minimal and moderate extrathyroidal invasion. ** indicates p < 0.01, *** indicates p < 0.001. Y axis is log10 normalized expression. (C) miR-126-3p expression is significantly lower in high and intermediate MACIS risk papillary thyroid cancer as compared to low MACIS risk tumors. MACIS is a prognostic scoring system used in the TCGA database which is based on the presence of Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size. ** indicates p < 0.01, *** indicates p < 0.001. Y axis is log10 normalized expression. (D) miR-126-3p expression is significantly lower in follicular thyroid cancer than follicular thyroid adenoma. All follicular thyroid cancer case had histologic evidence of capsular and vascular invasion and the adenomas did not have any evidence of capsular and vascular invasion. ** indicates p < 0.01. Y axis is 2^-(ΔΔCt).
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pone.0130496.g001: Lower miR-126-3p expression is associated with aggressive thyroid cancer.(A) miR-126-3p is significantly lower in larger papillary thyroid cancer (T3 compared to T2 and T1 tumors). Data for TCGA samples with available tumor size data. T1 tumors less than 2cm and not growing outside the thyroid, T2 tumors > 2cm but < 4cm and not growing outside the thyroid, T3 tumors measuring > 4cm or growing outside the thyroid. ** indicates p < 0.01, *** indicates p < 0.001. Y axis is log10 normalized expression. (B) miR-126-3p expression is significantly lower in papillary thyroid cancer with minimal and moderate extrathyroidal invasion. ** indicates p < 0.01, *** indicates p < 0.001. Y axis is log10 normalized expression. (C) miR-126-3p expression is significantly lower in high and intermediate MACIS risk papillary thyroid cancer as compared to low MACIS risk tumors. MACIS is a prognostic scoring system used in the TCGA database which is based on the presence of Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size. ** indicates p < 0.01, *** indicates p < 0.001. Y axis is log10 normalized expression. (D) miR-126-3p expression is significantly lower in follicular thyroid cancer than follicular thyroid adenoma. All follicular thyroid cancer case had histologic evidence of capsular and vascular invasion and the adenomas did not have any evidence of capsular and vascular invasion. ** indicates p < 0.01. Y axis is 2^-(ΔΔCt).

Mentions: We had previously identified miR-126-3p to be downregulated in thyroid cancers of follicular cell origin and in tumor types that were difficult-to-diagnose by tumor biopsy examination as capsular invasion and angioinvasion cannot be determine by cytology. Thus, we were interested in determining if miR-126-3p expression was associated with disease aggressiveness and specifically in tumors with capsular invasion and angioinvasion. To investigate this, we used the TCGA dataset for papillary thyroid cancer. We found that miR-126-3p expression was lower in larger primary tumors (Fig 1A), in tumor samples with extrathyroidal invasion (Fig 1B), and in high-risk group thyroid cancer (Fig 1C). Given the association of miR-126-3p with more aggressive papillary thyroid cancer, we next asked if miR-126-3p expression was lower in localized tumors with capsular invasion and angioinvasion using follicular thyroid cancer and adenomas samples for which malignancy is established only by the presence of these two hallmarks of cancer. We found miR-126-3p was significantly lower in localized follicular thyroid cancer as compared to follicular adenomas (Fig 1D). These findings taken together suggest that miR-126-3p may have a significant role in thyroid cancer initiation and or progression.


miR-126-3p Inhibits Thyroid Cancer Cell Growth and Metastasis, and Is Associated with Aggressive Thyroid Cancer.

Xiong Y, Kotian S, Zeiger MA, Zhang L, Kebebew E - PLoS ONE (2015)

Lower miR-126-3p expression is associated with aggressive thyroid cancer.(A) miR-126-3p is significantly lower in larger papillary thyroid cancer (T3 compared to T2 and T1 tumors). Data for TCGA samples with available tumor size data. T1 tumors less than 2cm and not growing outside the thyroid, T2 tumors > 2cm but < 4cm and not growing outside the thyroid, T3 tumors measuring > 4cm or growing outside the thyroid. ** indicates p < 0.01, *** indicates p < 0.001. Y axis is log10 normalized expression. (B) miR-126-3p expression is significantly lower in papillary thyroid cancer with minimal and moderate extrathyroidal invasion. ** indicates p < 0.01, *** indicates p < 0.001. Y axis is log10 normalized expression. (C) miR-126-3p expression is significantly lower in high and intermediate MACIS risk papillary thyroid cancer as compared to low MACIS risk tumors. MACIS is a prognostic scoring system used in the TCGA database which is based on the presence of Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size. ** indicates p < 0.01, *** indicates p < 0.001. Y axis is log10 normalized expression. (D) miR-126-3p expression is significantly lower in follicular thyroid cancer than follicular thyroid adenoma. All follicular thyroid cancer case had histologic evidence of capsular and vascular invasion and the adenomas did not have any evidence of capsular and vascular invasion. ** indicates p < 0.01. Y axis is 2^-(ΔΔCt).
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pone.0130496.g001: Lower miR-126-3p expression is associated with aggressive thyroid cancer.(A) miR-126-3p is significantly lower in larger papillary thyroid cancer (T3 compared to T2 and T1 tumors). Data for TCGA samples with available tumor size data. T1 tumors less than 2cm and not growing outside the thyroid, T2 tumors > 2cm but < 4cm and not growing outside the thyroid, T3 tumors measuring > 4cm or growing outside the thyroid. ** indicates p < 0.01, *** indicates p < 0.001. Y axis is log10 normalized expression. (B) miR-126-3p expression is significantly lower in papillary thyroid cancer with minimal and moderate extrathyroidal invasion. ** indicates p < 0.01, *** indicates p < 0.001. Y axis is log10 normalized expression. (C) miR-126-3p expression is significantly lower in high and intermediate MACIS risk papillary thyroid cancer as compared to low MACIS risk tumors. MACIS is a prognostic scoring system used in the TCGA database which is based on the presence of Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size. ** indicates p < 0.01, *** indicates p < 0.001. Y axis is log10 normalized expression. (D) miR-126-3p expression is significantly lower in follicular thyroid cancer than follicular thyroid adenoma. All follicular thyroid cancer case had histologic evidence of capsular and vascular invasion and the adenomas did not have any evidence of capsular and vascular invasion. ** indicates p < 0.01. Y axis is 2^-(ΔΔCt).
Mentions: We had previously identified miR-126-3p to be downregulated in thyroid cancers of follicular cell origin and in tumor types that were difficult-to-diagnose by tumor biopsy examination as capsular invasion and angioinvasion cannot be determine by cytology. Thus, we were interested in determining if miR-126-3p expression was associated with disease aggressiveness and specifically in tumors with capsular invasion and angioinvasion. To investigate this, we used the TCGA dataset for papillary thyroid cancer. We found that miR-126-3p expression was lower in larger primary tumors (Fig 1A), in tumor samples with extrathyroidal invasion (Fig 1B), and in high-risk group thyroid cancer (Fig 1C). Given the association of miR-126-3p with more aggressive papillary thyroid cancer, we next asked if miR-126-3p expression was lower in localized tumors with capsular invasion and angioinvasion using follicular thyroid cancer and adenomas samples for which malignancy is established only by the presence of these two hallmarks of cancer. We found miR-126-3p was significantly lower in localized follicular thyroid cancer as compared to follicular adenomas (Fig 1D). These findings taken together suggest that miR-126-3p may have a significant role in thyroid cancer initiation and or progression.

Bottom Line: We found that miR-126-3p expression was significantly lower in larger tumors, in tumor samples with extrathyroidal invasion, and in higher risk group thyroid cancer in 496 papillary thyroid cancer samples from The Cancer Genome Atlas study cohort.In an independent sample set, lower miR-126-3p expression was observed in follicular thyroid cancers (which have capsular and angioinvasion) as compared to follicular adenomas.Of these 14 genes, SLC7A5 and ADAM9 were confirmed to be inhibited by miR-126-3p overexpression and to be direct targets of miR-136-3p.

View Article: PubMed Central - PubMed

Affiliation: Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America.

ABSTRACT

Background: Previous studies have shown that microRNAs are dysregulated in thyroid cancer and play important roles in the post-transcriptional regulation of target oncogenes and/or tumor suppressor genes.

Methodology/principal findings: We studied the function of miR-126-3p in thyroid cancer cells, and as a marker of disease aggressiveness. We found that miR-126-3p expression was significantly lower in larger tumors, in tumor samples with extrathyroidal invasion, and in higher risk group thyroid cancer in 496 papillary thyroid cancer samples from The Cancer Genome Atlas study cohort. In an independent sample set, lower miR-126-3p expression was observed in follicular thyroid cancers (which have capsular and angioinvasion) as compared to follicular adenomas. Mechanistically, ectopic overexpression of miR-126-3p significantly inhibited thyroid cancer cell proliferation, in vitro (p<0.01) and in vivo (p<0.01), colony formation (p<0.01), tumor spheroid formation (p<0.05), cellular migration (p<0.05), VEGF secretion and endothelial tube formation, and lung metastasis in vivo. We found 14 predicted target genes, which were significantly altered upon miR-126-3p transfection in thyroid cancer cells, and which are involved in cancer biology. Of these 14 genes, SLC7A5 and ADAM9 were confirmed to be inhibited by miR-126-3p overexpression and to be direct targets of miR-136-3p.

Conclusions/significance: To our knowledge, this is the first study to demonstrate that miR-126-3p has a tumor-suppressive function in thyroid cancer cells, and is associated with aggressive disease phenotype.

No MeSH data available.


Related in: MedlinePlus