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miRs-134 and -370 function as tumor suppressors in colorectal cancer by independently suppressing EGFR and PI3K signalling.

El-Daly SM, Abba ML, Patil N, Allgayer H - Sci Rep (2016)

Bottom Line: Furthermore, overexpression of miR-134 or -370 resulted in a significant reduction of cell proliferation, colony formation, migration, invasion and in-vivo tumor growth and metastasis.Concurrent experiments with small interfering RNAs targeting the prime targets show that our selected miRNAs exert a greater functional influence and affect more downstream molecules than is seen with silencing of the individual proteins.Taken together, these data indicate that miRs-134 and -370 are potential tumour suppressor miRNAs and could play a fundamental role in suppressing colorectal cancer tumorigenesis through their ability to co-ordinately regulate EGFR signalling cascade by independently targeting EGFR and PIK3CA.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Germany.

ABSTRACT
Growth factor receptor signalling plays a central and critical role in colorectal cancer. Most importantly, the EGFR signalling cascade involving PI3K/AKT/mTOR and Raf/MEK/ERK pathways are particularly relevant, since they are commonly activated in several cancer entities, including colorectal cancer. In this study, we show that miRs-134 and -370 are both capable of regulating these pathways by targeting EGFR and PIK3CA. In three different colorectal cancer cell lines (DLD1, HCT-116 and RKO), suppression of EGFR and PIK3CA through the enhanced expression of miR-134 or -370 led to a suppression of the key molecules of the PI3K/AKT/mTOR pathway. Furthermore, overexpression of miR-134 or -370 resulted in a significant reduction of cell proliferation, colony formation, migration, invasion and in-vivo tumor growth and metastasis. Concurrent experiments with small interfering RNAs targeting the prime targets show that our selected miRNAs exert a greater functional influence and affect more downstream molecules than is seen with silencing of the individual proteins. Taken together, these data indicate that miRs-134 and -370 are potential tumour suppressor miRNAs and could play a fundamental role in suppressing colorectal cancer tumorigenesis through their ability to co-ordinately regulate EGFR signalling cascade by independently targeting EGFR and PIK3CA.

No MeSH data available.


Related in: MedlinePlus

miRs-134 and -370 are downregulated in resected human tumors and correlate inversely with EGFR and PIK3A expression.(a–d) Dot plots showing the relative tumor/normal expression of miRs-134 and -370 and that of the corresponding mRNA expression of EGFR and PIK3CA in a cohort of 25–30 patients. Both miR-134 and miR-370 are compared with EGFR and PIK3CA. In all cases, a predominant downregulation of the miRNAs together with a corresponding over-expression of the EGFR and PIK3CA mRNAs was observed. Both miRNAs were significantly downregulated in tumor compared to the corresponding normal samples (miR-134, p = 0.0077; miR-370, p = 0.00367).
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f6: miRs-134 and -370 are downregulated in resected human tumors and correlate inversely with EGFR and PIK3A expression.(a–d) Dot plots showing the relative tumor/normal expression of miRs-134 and -370 and that of the corresponding mRNA expression of EGFR and PIK3CA in a cohort of 25–30 patients. Both miR-134 and miR-370 are compared with EGFR and PIK3CA. In all cases, a predominant downregulation of the miRNAs together with a corresponding over-expression of the EGFR and PIK3CA mRNAs was observed. Both miRNAs were significantly downregulated in tumor compared to the corresponding normal samples (miR-134, p = 0.0077; miR-370, p = 0.00367).

Mentions: Following the experimental evidence supporting the significant impact of miRs-134 and 370 in modulating several tumorigenic processes, including metastasis, we decided to analyze the in vivo significance of these two miRNAs in human resected tumors. We screened a matched tumor/normal tissue series of (n = 30) resected colorectal cancer tissues for the expression of miRs-134 and -370 and observed a significant downregulation in tumor, compared to the corresponding normal samples. Likewise, we screened the prime targets of these miRNAs (EGFR and PIK3CA) and discovered that they were both significantly upregulated in the tumor tissues (Fig. 6a–d).


miRs-134 and -370 function as tumor suppressors in colorectal cancer by independently suppressing EGFR and PI3K signalling.

El-Daly SM, Abba ML, Patil N, Allgayer H - Sci Rep (2016)

miRs-134 and -370 are downregulated in resected human tumors and correlate inversely with EGFR and PIK3A expression.(a–d) Dot plots showing the relative tumor/normal expression of miRs-134 and -370 and that of the corresponding mRNA expression of EGFR and PIK3CA in a cohort of 25–30 patients. Both miR-134 and miR-370 are compared with EGFR and PIK3CA. In all cases, a predominant downregulation of the miRNAs together with a corresponding over-expression of the EGFR and PIK3CA mRNAs was observed. Both miRNAs were significantly downregulated in tumor compared to the corresponding normal samples (miR-134, p = 0.0077; miR-370, p = 0.00367).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837379&req=5

f6: miRs-134 and -370 are downregulated in resected human tumors and correlate inversely with EGFR and PIK3A expression.(a–d) Dot plots showing the relative tumor/normal expression of miRs-134 and -370 and that of the corresponding mRNA expression of EGFR and PIK3CA in a cohort of 25–30 patients. Both miR-134 and miR-370 are compared with EGFR and PIK3CA. In all cases, a predominant downregulation of the miRNAs together with a corresponding over-expression of the EGFR and PIK3CA mRNAs was observed. Both miRNAs were significantly downregulated in tumor compared to the corresponding normal samples (miR-134, p = 0.0077; miR-370, p = 0.00367).
Mentions: Following the experimental evidence supporting the significant impact of miRs-134 and 370 in modulating several tumorigenic processes, including metastasis, we decided to analyze the in vivo significance of these two miRNAs in human resected tumors. We screened a matched tumor/normal tissue series of (n = 30) resected colorectal cancer tissues for the expression of miRs-134 and -370 and observed a significant downregulation in tumor, compared to the corresponding normal samples. Likewise, we screened the prime targets of these miRNAs (EGFR and PIK3CA) and discovered that they were both significantly upregulated in the tumor tissues (Fig. 6a–d).

Bottom Line: Furthermore, overexpression of miR-134 or -370 resulted in a significant reduction of cell proliferation, colony formation, migration, invasion and in-vivo tumor growth and metastasis.Concurrent experiments with small interfering RNAs targeting the prime targets show that our selected miRNAs exert a greater functional influence and affect more downstream molecules than is seen with silencing of the individual proteins.Taken together, these data indicate that miRs-134 and -370 are potential tumour suppressor miRNAs and could play a fundamental role in suppressing colorectal cancer tumorigenesis through their ability to co-ordinately regulate EGFR signalling cascade by independently targeting EGFR and PIK3CA.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Germany.

ABSTRACT
Growth factor receptor signalling plays a central and critical role in colorectal cancer. Most importantly, the EGFR signalling cascade involving PI3K/AKT/mTOR and Raf/MEK/ERK pathways are particularly relevant, since they are commonly activated in several cancer entities, including colorectal cancer. In this study, we show that miRs-134 and -370 are both capable of regulating these pathways by targeting EGFR and PIK3CA. In three different colorectal cancer cell lines (DLD1, HCT-116 and RKO), suppression of EGFR and PIK3CA through the enhanced expression of miR-134 or -370 led to a suppression of the key molecules of the PI3K/AKT/mTOR pathway. Furthermore, overexpression of miR-134 or -370 resulted in a significant reduction of cell proliferation, colony formation, migration, invasion and in-vivo tumor growth and metastasis. Concurrent experiments with small interfering RNAs targeting the prime targets show that our selected miRNAs exert a greater functional influence and affect more downstream molecules than is seen with silencing of the individual proteins. Taken together, these data indicate that miRs-134 and -370 are potential tumour suppressor miRNAs and could play a fundamental role in suppressing colorectal cancer tumorigenesis through their ability to co-ordinately regulate EGFR signalling cascade by independently targeting EGFR and PIK3CA.

No MeSH data available.


Related in: MedlinePlus