Abstract
The GTPase K-ras is involved in a variety of cellular processes such as differentiation, proliferation and survival. However, activating mutations, which frequently occur in many types of cancer, turn KRAS into one of the most prominent oncogenes. Likewise, miR-200c is a key player in tumorigenesis functioning as a molecular switch between an epithelial, non-migratory, chemosensitive and a mesenchymal, migratory, chemoresistant state. While it has been reported that KRAS is modulated by several tumor suppressor miRNAs, this is the first report on the regulation of KRAS by miR-200c, both playing a pivotal role in oncogenesis. We show that KRAS is a predicted target of miR-200c and that the protein expression of KRAS inversely correlates with the miR-200c expression in a panel of human breast cancer cell lines. KRAS was experimentally validated as a target of miR-200c by Western blot analyses and luciferase reporter assays. Furthermore, the inhibitory effect of miR-200c-dependent KRAS silencing on proliferation and cell cycle was demonstrated in different breast and lung cancer cell lines. Thereby, the particular role of KRAS was dissected from the role of all the other miR-200c targets by specific knockdown experiments using siRNA against KRAS. Cell lines harboring an activating KRAS mutation were similarly affected by miR-200c as well as by the siRNA against KRAS. However, in a cell line with wild-type KRAS only miR-200c was able to change proliferation and cell cycle. Our findings suggest that miR-200c is a potent inhibitor of tumor progression and therapy resistance, by regulating a multitude of oncogenic pathways including the RAS pathway. Thus, miR-200c may cause stronger anti-tumor effects than a specific siRNA against KRAS, emphasizing the potential role of miR-200c as tumor suppressive miRNA.
Highlights
In cancer, many cellular processes such as differentiation, growth, migration and survival, are regulated by GTPases of the RAS family
While it has been reported that KRAS is modulated by several tumor suppressor miRNAs, this is the first report on the regulation of KRAS by miR-200c, both playing a pivotal role in oncogenesis
We show that KRAS is a predicted target of miR-200c and that the protein expression of KRAS inversely correlates with the miR-200c expression in a panel of human breast cancer cell lines
Summary
Many cellular processes such as differentiation, growth, migration and survival, are regulated by GTPases of the RAS family. Amongst them K-ras plays a pivotal role in oncogenesis due to its capability of transforming human cells into malignant tumor cells when harboring an activating mutation in codon 12 or 13. KRAS mutations frequently occur in many types of human tumors, for example 70 – 90% in pancreas, 30 – 60% in colon and 15 – 50% in lung, making KRAS one of the most prominent oncogenes [1, 2]. Activating oncogenic KRAS mutations are often associated with resistance to chemotherapy and targeted therapies [2,3,4,5,6]. Due to the poor prognosis for cancer patients with mutated KRAS, much effort has been spent on developing specific therapies for targeting oncogenic KRAS. Apart from specific RNAi methods, up to now there are no small molecules available which can target K-ras
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