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MiR-139-5p inhibits migration and invasion of colorectal cancer by downregulating AMFR and NOTCH1.

Song M, Yin Y, Zhang J, Zhang B, Bian Z, Quan C, Zhou L, Hu Y, Wang Q, Ni S, Fei B, Wang W, Du X, Hua D, Huang Z - Protein Cell (2014)

Bottom Line: We found that miR-139-5p was significantly downregulated in 73.8% CRC samples compared with adjacent noncancerous tissues (NCTs), and decreased miR-139-5p was associated with poor prognosis.Furthermore, the protein levels of the two genes were upregulated in CRC samples compared with NCTs, and inversely correlated with the miR-139-5p expression.Increased NOTCH1 protein expression was correlated with poor prognosis of CRC patients.

View Article: PubMed Central - PubMed

Affiliation: Wuxi Oncology Institute, the Affiliated Hospital of Jiangnan University, Wuxi, 214062, China.

ABSTRACT
MicroRNAs (miRNAs) that exert function by posttranscriptional suppression have recently brought insight in our understanding of the role of non-protein-coding RNAs in carcinogenesis and metastasis. In this study, we described the function and molecular mechanism of miR-139-5p in colorectal cancer (CRC) and its potential clinical application in CRC. We found that miR-139-5p was significantly downregulated in 73.8% CRC samples compared with adjacent noncancerous tissues (NCTs), and decreased miR-139-5p was associated with poor prognosis. Functional analyses demonstrated that ectopic expression of miR-139-5p suppressed CRC cell migration and invasion in vitro and metastasis in vivo. Mechanistic investigations revealed that miR-139-5p suppress CRC cell invasion and metastasis by targeting AMFR and NOTCH1. Knockdown of the two genes phenocopied the inhibitory effect of miR-139-5p on CRC metastasis. Furthermore, the protein levels of the two genes were upregulated in CRC samples compared with NCTs, and inversely correlated with the miR-139-5p expression. Increased NOTCH1 protein expression was correlated with poor prognosis of CRC patients. Together, our data indicate that miR-139-5p is a potential tumor suppressor and prognostic factor for CRC, and targeting miR-139-5p may repress the metastasis of CRC and improve survival.

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miR-139-5p is frequently downregulated and associated with poor overall survival in CRC. (A) MiR-139-5p expression was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 80 paired CRC and adjacent noncancerous tissues (NCTs). MiR-139-5p expression was markedly downregulated in tumor tissues compared with the corresponding NCTs (U6 small nuclear RNA was used as an internal control). (B) Overall survival analysis based on the expression level of miR-139-5p. MiR-139-5p expression was examined in 158 CRC tissues, and these cases were divided into two groups (high or low) or four groups (1–4) based on their miR-139-5p levels in tumors. MiR-139-5p expression was positively correlated with the overall survival
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Fig1: miR-139-5p is frequently downregulated and associated with poor overall survival in CRC. (A) MiR-139-5p expression was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 80 paired CRC and adjacent noncancerous tissues (NCTs). MiR-139-5p expression was markedly downregulated in tumor tissues compared with the corresponding NCTs (U6 small nuclear RNA was used as an internal control). (B) Overall survival analysis based on the expression level of miR-139-5p. MiR-139-5p expression was examined in 158 CRC tissues, and these cases were divided into two groups (high or low) or four groups (1–4) based on their miR-139-5p levels in tumors. MiR-139-5p expression was positively correlated with the overall survival

Mentions: Our data of miRNA expression profile have demonstrated that miR-139-5p is downregulated in CRCs compared to NCTs (Huang et al. 2011). To further verify the result, the expression level of miR-139-5p was examined using qRT-PCR in an expanded cohort of 158 CRCs, including 80 tumors with paired NCTs. In accordance with the microarray data, the results showed that miR-139-5p was downregulated more than 2-fold in 73.8% of CRCs compared with NCTs (P < 0.0001, Fig. 1A). Survival analysis showed that high miR-139-5p expression was associated with prolonged overall survival of CRC patients (high: the 25% highest, low: the 25% lowest) (P < 0.05, Fig. 1B). After adjustment for age, gender, tumor size, pathologic stage, and grading, a Cox multivariate analysis indicated that miR-139-5p expression is an independent prognostic factor for CRC (adjusted HR = 2.681, 95% CI = 1.532–4.691, P = 0.001, Table S1). No significant relationship was found between miR-139-5p expression in CRC and tumor size, location, stage, and grading (P > 0.05).Figure 1


MiR-139-5p inhibits migration and invasion of colorectal cancer by downregulating AMFR and NOTCH1.

Song M, Yin Y, Zhang J, Zhang B, Bian Z, Quan C, Zhou L, Hu Y, Wang Q, Ni S, Fei B, Wang W, Du X, Hua D, Huang Z - Protein Cell (2014)

miR-139-5p is frequently downregulated and associated with poor overall survival in CRC. (A) MiR-139-5p expression was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 80 paired CRC and adjacent noncancerous tissues (NCTs). MiR-139-5p expression was markedly downregulated in tumor tissues compared with the corresponding NCTs (U6 small nuclear RNA was used as an internal control). (B) Overall survival analysis based on the expression level of miR-139-5p. MiR-139-5p expression was examined in 158 CRC tissues, and these cases were divided into two groups (high or low) or four groups (1–4) based on their miR-139-5p levels in tumors. MiR-139-5p expression was positively correlated with the overall survival
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4225484&req=5

Fig1: miR-139-5p is frequently downregulated and associated with poor overall survival in CRC. (A) MiR-139-5p expression was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 80 paired CRC and adjacent noncancerous tissues (NCTs). MiR-139-5p expression was markedly downregulated in tumor tissues compared with the corresponding NCTs (U6 small nuclear RNA was used as an internal control). (B) Overall survival analysis based on the expression level of miR-139-5p. MiR-139-5p expression was examined in 158 CRC tissues, and these cases were divided into two groups (high or low) or four groups (1–4) based on their miR-139-5p levels in tumors. MiR-139-5p expression was positively correlated with the overall survival
Mentions: Our data of miRNA expression profile have demonstrated that miR-139-5p is downregulated in CRCs compared to NCTs (Huang et al. 2011). To further verify the result, the expression level of miR-139-5p was examined using qRT-PCR in an expanded cohort of 158 CRCs, including 80 tumors with paired NCTs. In accordance with the microarray data, the results showed that miR-139-5p was downregulated more than 2-fold in 73.8% of CRCs compared with NCTs (P < 0.0001, Fig. 1A). Survival analysis showed that high miR-139-5p expression was associated with prolonged overall survival of CRC patients (high: the 25% highest, low: the 25% lowest) (P < 0.05, Fig. 1B). After adjustment for age, gender, tumor size, pathologic stage, and grading, a Cox multivariate analysis indicated that miR-139-5p expression is an independent prognostic factor for CRC (adjusted HR = 2.681, 95% CI = 1.532–4.691, P = 0.001, Table S1). No significant relationship was found between miR-139-5p expression in CRC and tumor size, location, stage, and grading (P > 0.05).Figure 1

Bottom Line: We found that miR-139-5p was significantly downregulated in 73.8% CRC samples compared with adjacent noncancerous tissues (NCTs), and decreased miR-139-5p was associated with poor prognosis.Furthermore, the protein levels of the two genes were upregulated in CRC samples compared with NCTs, and inversely correlated with the miR-139-5p expression.Increased NOTCH1 protein expression was correlated with poor prognosis of CRC patients.

View Article: PubMed Central - PubMed

Affiliation: Wuxi Oncology Institute, the Affiliated Hospital of Jiangnan University, Wuxi, 214062, China.

ABSTRACT
MicroRNAs (miRNAs) that exert function by posttranscriptional suppression have recently brought insight in our understanding of the role of non-protein-coding RNAs in carcinogenesis and metastasis. In this study, we described the function and molecular mechanism of miR-139-5p in colorectal cancer (CRC) and its potential clinical application in CRC. We found that miR-139-5p was significantly downregulated in 73.8% CRC samples compared with adjacent noncancerous tissues (NCTs), and decreased miR-139-5p was associated with poor prognosis. Functional analyses demonstrated that ectopic expression of miR-139-5p suppressed CRC cell migration and invasion in vitro and metastasis in vivo. Mechanistic investigations revealed that miR-139-5p suppress CRC cell invasion and metastasis by targeting AMFR and NOTCH1. Knockdown of the two genes phenocopied the inhibitory effect of miR-139-5p on CRC metastasis. Furthermore, the protein levels of the two genes were upregulated in CRC samples compared with NCTs, and inversely correlated with the miR-139-5p expression. Increased NOTCH1 protein expression was correlated with poor prognosis of CRC patients. Together, our data indicate that miR-139-5p is a potential tumor suppressor and prognostic factor for CRC, and targeting miR-139-5p may repress the metastasis of CRC and improve survival.

Show MeSH
Related in: MedlinePlus