Abstract
N-myc and STAT interactor (NMI) has been proved to bind to different transcription factors to regulate a variety of signaling mechanisms including DNA damage, cell cycle and epithelial–mesenchymal transition. However, the role of NMI in the regulation of cancer stem cells (CSCs) remains poorly understood. In this study, we investigated the regulation of NMI on CSCs traits in breast cancer and uncovered the underlying molecular mechanisms. We found that NMI was lowly expressed in breast cancer stem cells (BCSCs)-enriched populations. Knockdown of NMI promoted CSCs traits while its overexpression inhibited CSCs traits, including the expression of CSC-related markers, the number of CD44+CD24− cell populations and the ability of mammospheres formation. We also found that NMI-mediated regulation of BCSCs traits was at least partially realized through the modulation of hTERT signaling. NMI knockdown upregulated hTERT expression while its overexpression downregulated hTERT in breast cancer cells, and the changes in CSCs traits and cell invasion ability mediated by NMI were rescued by hTERT. The in vivo study also validated that NMI knockdown promoted breast cancer growth by upregulating hTERT signaling in a mouse model. Moreover, further analyses for the clinical samples demonstrated that NMI expression was negatively correlated with hTERT expression and the low NMI/high hTERT expression was associated with the worse status of clinical TNM stages in breast cancer patients. Furthermore, we demonstrated that the interaction of YY1 protein with NMI and its involvement in NMI-mediated transcriptional regulation of hTERT in breast cancer cells. Collectively, our results provide new insights into understanding the regulatory mechanism of CSCs and suggest that the NMI-YY1-hTERT signaling axis may be a potential therapeutic target for breast cancers.
Highlights
Breast cancer is one of the leading mortal causes from cancer among women worldwide.[1,2] Surgery, radiotherapy, chemotherapy and hormone therapy are still the main and common therapeutic approaches to treat breast cancer.[3]
Combined with the analysis from the clinical samples demonstrating that NMI expression was inversely correlated with Human telomerase reverse transcriptase (hTERT) and the low NMI/high hTERT expression was associated with the worse status of clinical TNM stages in breast cancer patients, our findings may provide new insights into identifying the unknown central proteins involved in regulating breast cancer stem cells (BCSCs) traits, understanding the underlying regulatory mechanism of such regulation and exploring new therapeutic targets for breast cancer treatment
And f, the expression of NMI was downregulated in breast cancer mammospheres compared with primary breast cancer (Figure 1e) and NMI was downregulated in the CD44+CD24− cells compared with the CD44−CD24+ cell populations (Figure 1f). These results indicate that NMI is downregulated in the BCSCs-enriched populations
Summary
Breast cancer is one of the leading mortal causes from cancer among women worldwide.[1,2] Surgery, radiotherapy, chemotherapy and hormone therapy are still the main and common therapeutic approaches to treat breast cancer.[3]. Cancer stem cells (CSCs), including breast cancer stem cells (BCSCs), have been shown to play important roles in cancer’s recurrence and metastasis.[4,5,6] BCSCs are relatively resistant to chemotherapy and radiotherapy compared with their non-tumorigenic progeny.[7,8,9] it is necessary to discover and identify the novel and specific molecular targets and their related signaling pathways to inhibit the mammary stem/progenitor cell population and suppress carcinogenesis and tumor metastasis. Combined with the analysis from the clinical samples demonstrating that NMI expression was inversely correlated with hTERT and the low NMI/high hTERT expression was associated with the worse status of clinical TNM stages in breast cancer patients, our findings may provide new insights into identifying the unknown central proteins involved in regulating BCSCs traits, understanding the underlying regulatory mechanism of such regulation and exploring new therapeutic targets for breast cancer treatment
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