miRs-134 and -370 function as tumor suppressors in colorectal cancer by independently suppressing EGFR and PI3K signalling.
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.
Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Germany.|Centre for Biomedicine and Medical Technology (CBTM) Mannheim, University of Heidelberg, Germany.|Department of Medical Biochemistry, Medical Division, National Research Centre, Cairo, Egypt.
Sherien M
SM
El-Daly
Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Germany.|Centre for Biomedicine and Medical Technology (CBTM) Mannheim, University of Heidelberg, Germany.
Mohammed L
ML
Abba
Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Germany.|Centre for Biomedicine and Medical Technology (CBTM) Mannheim, University of Heidelberg, Germany.
Nitin
N
Patil
Department of Experimental Surgery, Medical Faculty Mannheim, University of Heidelberg, Germany.|Centre for Biomedicine and Medical Technology (CBTM) Mannheim, University of Heidelberg, Germany.
Heike
H
Allgayer
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D047368:Tumor Burden
D066246:ErbB Receptors; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C569273:MIRN134 microRNA, human; C526503:MIRN370 microRNA, human