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Increased microRNA-34b and -34c predominantly expressed in stromal tissues is associated with poor prognosis in human colon cancer.

Hiyoshi Y, Schetter AJ, Okayama H, Inamura K, Anami K, Nguyen GH, Horikawa I, Hawkes JE, Bowman ED, Leung SY, Harris CC - PLoS ONE (2015)

Bottom Line: To examine where the miR-34 family is expressed, the expression of miR-34 family was compared between epitheliums and stromal tissues using laser microdissection technique.In conclusion, increased miR-34b/c predominantly expressed in stromal tissues is associated with poor prognosis in colon cancer.MiR-34 may contribute to cancer-stromal interaction associated with colon cancer progression.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

ABSTRACT
The microRNA-34 family (miR-34a, -34b and -34c) have been reported to be tumor suppressor microRNAs (miRNAs) that are regulated by the TP53 and DNA hypermethylation. However, the expression, regulation, and prognostic value of the miR-34 family have not been systematically studied in colon cancer. To elucidate the roles of miR-34 family in colon carcinogenesis, miR-34a/b/c were measured in tumors and adjacent noncancerous tissues from 159 American and 113 Chinese colon cancer patients using quantitative RT-PCR, and we examined associations between miR-34a/b/c expression with TNM staging, cancer-specific mortality, TP53 mutation status and Affymetrix microarray data. All miR-34 family members were significantly increased in colon tumors, counter to the proposed tumor suppressor role for these miRNAs. Increased miR-34b/c were observed in more advanced tumors in two independent cohorts and increased expression of miR-34b/c was associated with poor cancer-specific mortality. While the expression of miR-34 family was not associated with TP53 mutation status, TP53 transcriptional activity was associated with miR-34a/b/c expression that is consistent with the proposed regulation of miR-34a/b/c by TP53. To examine where the miR-34 family is expressed, the expression of miR-34 family was compared between epitheliums and stromal tissues using laser microdissection technique. The expression of miR-34b/c was increased significantly in stromal tissues, especially in cancer stroma, compared with epithelial tissue. In conclusion, increased miR-34b/c predominantly expressed in stromal tissues is associated with poor prognosis in colon cancer. MiR-34 may contribute to cancer-stromal interaction associated with colon cancer progression.

No MeSH data available.


Related in: MedlinePlus

miR-34 family tends to be expressed predominantly in stromal tissue.RNA samples from cancer epithelium, cancer stroma, normal adjacent epithelium and normal adjacent stroma were extracted separately using laser microdissection technique from 5 paired samples in the American cohort. Dot plots represent miR-34a/b/c threshold cycle values of tumor tissue from TaqMan qRT-PCR normalized to U48. Horizontal bars indicate median expression value. Un-paired t test was used.
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pone.0124899.g004: miR-34 family tends to be expressed predominantly in stromal tissue.RNA samples from cancer epithelium, cancer stroma, normal adjacent epithelium and normal adjacent stroma were extracted separately using laser microdissection technique from 5 paired samples in the American cohort. Dot plots represent miR-34a/b/c threshold cycle values of tumor tissue from TaqMan qRT-PCR normalized to U48. Horizontal bars indicate median expression value. Un-paired t test was used.

Mentions: Altered expression of oncogenic miRNAs in colorectal cancer stromal tissue might be associated with cancer progression [23]. To examine where the miR-34 family is expressed in, we extracted RNA from cancer epithelium, cancer stroma, normal adjacent epithelium and normal adjacent stroma separately using laser microdissection for miR-34 expression analysis (S3 Fig). Five colon tumor and 5 adjacent non-tumor frozen tissue samples were obtained form the American cohort. MiR-34b and -34c expression levels in stroma were significantly higher as compared with that of epithelium in both cancer tissues and in normal adjacent tissues (Fig 4 middle and right panels). MiR-34a showed similar trend although the differences were not significant (Fig 4 left panel). We further examined the publicly available microarray dataset (GSE35602), in which miRNA expression profiles of micro-dissected colon cancer stromal and epithelial tissues were analyzed, demonstrating a clear trend of higher miR-34b and -34c expression in cancer stroma (S4 Fig). This microarray data are consistent with our own qRT-PCR analysis using LMD samples, indicating that miR-34b and -34c are expressed at higher levels in stomal tissues. In addition, we have performed H&E on 82 of the tissues from the American cohort to examine if there was an association with increased stromal area and any of the miR-34 family. There was no significant correlation between tumor/stroma ratio and expression levels of miR-34 (S5 Fig). These findings based on LMD analyses suggest that stromal cells serve the major source of miR-34b/c rather than epithelial cells. Hence, miR-34b/c expression detected in macro-dissected tumor samples (as shown in Fig 1) seems to mainly represent stromal expression of miR-34b/c.


Increased microRNA-34b and -34c predominantly expressed in stromal tissues is associated with poor prognosis in human colon cancer.

Hiyoshi Y, Schetter AJ, Okayama H, Inamura K, Anami K, Nguyen GH, Horikawa I, Hawkes JE, Bowman ED, Leung SY, Harris CC - PLoS ONE (2015)

miR-34 family tends to be expressed predominantly in stromal tissue.RNA samples from cancer epithelium, cancer stroma, normal adjacent epithelium and normal adjacent stroma were extracted separately using laser microdissection technique from 5 paired samples in the American cohort. Dot plots represent miR-34a/b/c threshold cycle values of tumor tissue from TaqMan qRT-PCR normalized to U48. Horizontal bars indicate median expression value. Un-paired t test was used.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4404052&req=5

pone.0124899.g004: miR-34 family tends to be expressed predominantly in stromal tissue.RNA samples from cancer epithelium, cancer stroma, normal adjacent epithelium and normal adjacent stroma were extracted separately using laser microdissection technique from 5 paired samples in the American cohort. Dot plots represent miR-34a/b/c threshold cycle values of tumor tissue from TaqMan qRT-PCR normalized to U48. Horizontal bars indicate median expression value. Un-paired t test was used.
Mentions: Altered expression of oncogenic miRNAs in colorectal cancer stromal tissue might be associated with cancer progression [23]. To examine where the miR-34 family is expressed in, we extracted RNA from cancer epithelium, cancer stroma, normal adjacent epithelium and normal adjacent stroma separately using laser microdissection for miR-34 expression analysis (S3 Fig). Five colon tumor and 5 adjacent non-tumor frozen tissue samples were obtained form the American cohort. MiR-34b and -34c expression levels in stroma were significantly higher as compared with that of epithelium in both cancer tissues and in normal adjacent tissues (Fig 4 middle and right panels). MiR-34a showed similar trend although the differences were not significant (Fig 4 left panel). We further examined the publicly available microarray dataset (GSE35602), in which miRNA expression profiles of micro-dissected colon cancer stromal and epithelial tissues were analyzed, demonstrating a clear trend of higher miR-34b and -34c expression in cancer stroma (S4 Fig). This microarray data are consistent with our own qRT-PCR analysis using LMD samples, indicating that miR-34b and -34c are expressed at higher levels in stomal tissues. In addition, we have performed H&E on 82 of the tissues from the American cohort to examine if there was an association with increased stromal area and any of the miR-34 family. There was no significant correlation between tumor/stroma ratio and expression levels of miR-34 (S5 Fig). These findings based on LMD analyses suggest that stromal cells serve the major source of miR-34b/c rather than epithelial cells. Hence, miR-34b/c expression detected in macro-dissected tumor samples (as shown in Fig 1) seems to mainly represent stromal expression of miR-34b/c.

Bottom Line: To examine where the miR-34 family is expressed, the expression of miR-34 family was compared between epitheliums and stromal tissues using laser microdissection technique.In conclusion, increased miR-34b/c predominantly expressed in stromal tissues is associated with poor prognosis in colon cancer.MiR-34 may contribute to cancer-stromal interaction associated with colon cancer progression.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

ABSTRACT
The microRNA-34 family (miR-34a, -34b and -34c) have been reported to be tumor suppressor microRNAs (miRNAs) that are regulated by the TP53 and DNA hypermethylation. However, the expression, regulation, and prognostic value of the miR-34 family have not been systematically studied in colon cancer. To elucidate the roles of miR-34 family in colon carcinogenesis, miR-34a/b/c were measured in tumors and adjacent noncancerous tissues from 159 American and 113 Chinese colon cancer patients using quantitative RT-PCR, and we examined associations between miR-34a/b/c expression with TNM staging, cancer-specific mortality, TP53 mutation status and Affymetrix microarray data. All miR-34 family members were significantly increased in colon tumors, counter to the proposed tumor suppressor role for these miRNAs. Increased miR-34b/c were observed in more advanced tumors in two independent cohorts and increased expression of miR-34b/c was associated with poor cancer-specific mortality. While the expression of miR-34 family was not associated with TP53 mutation status, TP53 transcriptional activity was associated with miR-34a/b/c expression that is consistent with the proposed regulation of miR-34a/b/c by TP53. To examine where the miR-34 family is expressed, the expression of miR-34 family was compared between epitheliums and stromal tissues using laser microdissection technique. The expression of miR-34b/c was increased significantly in stromal tissues, especially in cancer stroma, compared with epithelial tissue. In conclusion, increased miR-34b/c predominantly expressed in stromal tissues is associated with poor prognosis in colon cancer. MiR-34 may contribute to cancer-stromal interaction associated with colon cancer progression.

No MeSH data available.


Related in: MedlinePlus