In our previous study, microarray analysis identified 246 genes significantly changed by stably knock down of XB130 in WRO thyroid cancer cells. Especially, 57 out of the 246 genes are related to cell proliferation or survival, including many transcription regulators 
. It has been estimated that approximately 30% of all human genes can be regulated by miRNAs 
. The alterations in the miRNA processing contributes to tumorigenesis 
. Therefore, we hypothesized that XB130 may regulate expression of growth-related miRNAs and subsequently control genes related to cell proliferation and survival. To evaluate this hypothesis, we analyzed miRNA expression in XB130 knockdown WRO cells. MicroRNA array analysis data showed that 38 miRNAs were differently expressed in XB130 knockdown cells. Among them, we focused on miR-33a, miR-149 and miR-193a-3p that have been reported as tumor suppressive miRNAs in various cancers. MiR-33a decelerates cell proliferation acting through inhibition of proto-oncogene Pim-1 in lymphoma and colon cancer cells 
. miR-149 expression has a direct correlation with KCNMA1 and LOX oncogenes in clear cell renal cell carcinoma 
. Similarly, miR-193-3p targets JNK1 and inhibits cell-cycle progression and proliferation in breast cancer 
. We validated up-regulation of miR-33a, miR-149 and miR-193a-3p in XB130 knockdown cells by real-time qRT-PCR.
In microRNA expression processes, RNA polymerase II produces long primary miRNA transcripts called pri-miRNAs, which are cropped and cleaved by a multi-protein complex including DROSHA and DICER1 to produce mature functional miRNAs 
. How the miRNA expression is regulated is still unclear, yet various mechanisms have been suggested. It has been shown that p53 was responsible for the post-transcriptional maturation of miR-16-1, miR-143 and miR-145, whereas expression of related pri-miRNAs was not influenced by p53 
. On the other hand, BRCA1 controls miR-155 expression by regulating a transcription mechanism 
. In the present study, the expression of pri-mir-33a, miR-149 and miR-193a-3p was also increased in XB130 knockdown cells, suggesting that XB130 may affect the transcription of these pri-miRNAs and subsequently affect the levels of mature miRNAs.
We also over-expressed XB130 in MRO thyroid cancer cells, which have very low levels of XB130. Schweppe et al. have found cross-contamination among commonly used thyroid cancer cell lines. MRO cells used in that study was suspected to be an HT-29 colon cancer derived cell line 
. Our results need to be interpreted with cautions. Nonetheless, overexpression of XB130 significantly reduced expression of these 3 miRNAs, both mature miRNAs and pri-miRNAs. Moreover, this regulatory effect was inhibited by deletion of the N-terminus of XB130. The N-terminal region of XB130 includes several tyrosine phosphorylation sites and a proline-rich sequence that could interact with Src homology 2 and 3 domain-containing proteins, such as Src and p85α subunit of PI3K 
. These data indicate that the regulation of these miRNAs by XB130 may be mediated trough specific signal transduction pathways.
We also examined the functions of these miRNAs on regulation of their predicted target genes and on cell proliferation in WRO cells. Firstly, overexpressed mimics of these miRNAs reduced the expression of their predicted target protein. Moreover, these miRNAs may directly bind to 3′UTR of targeted genes, as shown by the luciferase reporter assays. Interestingly, all three genes whose protein levels are down-regulated by overexpression of related miRNAs are known as oncogene. MYC, c-Myc-encoded protein, functions in cell proliferation and differentiation in several types of human cancers, including lung, breast, colon and thyroid cancers 
. FOSL1 has proto-oncogene function by dimerizing with proteins of the Jun family to form AP-1 complex, a transcription factor that controls critical cellular processes including differentiation, proliferation, and apoptosis 
. Kim et al., have reported thyroid malignant tumors have higher expression of FOSL1 (also called Fra-1) than in benign tumors 
. SLC7A5 (also called LAT1) is overexpressed in many cancer types, and its expression levels are usually correlated to cancer progression, aggressiveness and prognosis 
. SLC7A5 siRNA significantly reduced proliferation of small cell lung cancer cells 
and KB human oral cancer cells 
. Indeed, overexpression of miR-33a, miR-149 and miR-193a-3p resulted in inhibition of cell growth. Taken together, our results support tumor-suppressive functions for miR-33a, miR-149 and miR-193a-3p through down-regulation of related oncogene.
In summary, this study demonstrates a novel pro-oncogenic mechanism of XB130, regulating oncogenes through tumor suppressive miRNAs. It is plausible that some of the miRNAs decreased by XB130 knockdown might suppress other target genes (such as cell cycle inhibitors). miRNAs have been proposed as therapeutic targets for cancers 
. Therefore, how XB130 expression controls miRNA transcription and processing, and how XB130 related miRNA affects down-stream proteins, and consequently affect cell proliferation and survival may provide new knowledge in cancer research.