The role of miR-200a in mammalian epithelial cell transformation

Abstract

Cancer is a multistep disease that begins with malignant cell transformation and frequently culminates in metastasis. MicroRNAs (miRNAs) are small regulatory 21-25 nt RNA molecules and are frequently deregulated in cancer. miR-200a is a member of the miR-200 family, which are known inhibitors of the epithelial-to-mesenchymal transition. As such, the tumor-suppressive role of miR-200a in oncogenesis has been well documented; however, recent studies have found a proliferative role for this miRNA as well as a prometastatic role in the later steps of cancer progression. Little is known about the role of this miRNA in the early stages of cancer, namely, malignant cell transformation. Here, we show that miR-200a alone transforms an immortalized rat epithelial cell line, and miR-200a cooperates with Ras to enhance malignant transformation of an immortalized human epithelial cell line. Furthermore, miR-200a induces cell transformation and tumorigenesis in immunocompromised mice by cooperating with a Ras mutant that activates only the RalGEF effector pathway, but not Ras mutants activating PI3K or Raf effector pathways. This transformative ability is in accordance with miR-200a targeting Fog2 and p53 to activate Akt and directly repress p53 protein levels, respectively. These results demonstrate an oncogenic role for miR-200a and provide a specific cellular context where miR-200a acts as an oncomiR rather than a tumor suppressor by cooperating with an oncogene in malignant cell transformation.

Cellular and extracellular vesicular origins of miRNAs within the bovine ovarian follicle

“…Of the GC‐specific miRNAs, miR‐449a (Yao et al., ) and miR‐451 (Li, Zhang, Cai, & Bian, ; Tian et al., ) are reportedly associated with the PI3K‐Akt signalling pathway, while miR‐449a was recently found to be associated with Wnt signalling (Noferesti et al., ). Of the COC‐specific miRNAs, miR‐105 (Shen et al., ), miR‐126 (Kim et al., ) and miR‐200a (Becker, Takwi, Lu, & Li, ) were previously associated with the PI3K‐Akt signalling pathway, mirR‐218 and miR‐219‐5p were found to be associated the Wnt signalling pathway (Hu et al., ; Li, Dong, Han, & Zhang, ), and miR‐126 was determined to be associated with MAPK signalling (Chakraborty, Sharma, & Patra, ). Similarly, the association between follicular development and miRNA‐controlled signalling pathways such as the PI3K‐Akt, Wnt and MAPK signalling pathways has been demonstrated in both theca and GCs (Zielak‐Steciwko et al., ).…”

Tumor suppressive microRNA-200a inhibits renal cell carcinoma development by directly targeting TGFB2

“…There is growing evidence that miR-200 plays a vital role in tumor suppression by inhibiting EMT process, the initiating step of metastasis [23,24]. Downregulation of miR-200a has been reported in several human cancers, including nasopharyngeal carcinoma [12], meningiomas [25], and breast cancer [26].…”

Thymosin beta 4 up‐regulates miR‐200a expression and induces differentiation and survival of rat brain progenitor cells

“…; Becker et al . ). We therefore examined the effect of miR‐200a on the expression of FOG2 and PTEN, and AKT activation in the rat SVZ‐neurospheres and primary OPCs.…”

“…These data indicated that Tb4 treatment induced AKT activation in miR-200a dependent pathway, and suggested that miR-200a may target endogenous PI3K/ AKT inhibitors. Two miR-200a targets, FOG2 and PTEN, negatively regulate PI3K/AKT pathway (Hyun et al 2009;Li et al 2014;Yang et al 2014;Becker et al 2015). We therefore examined the effect of miR-200a on the expression of FOG2 and PTEN, and AKT activation in the rat SVZneurospheres and primary OPCs.…”