| Summary: | 博士 === 國立陽明大學 === 臨床醫學研究所 === 102 === The high invasiveness and frequent recurrence of lung adenocarcinoma (LAC) are major reasons for treatment failures and poor prognoses. MicroRNAs (miRNAs) are short non-coding RNAs that post-transcriptionally regulate gene expression. Numerous studies have shown that miRNAs are crucial regulators of cancer pathways and alternations in miRNAs expression can contribute to tumorigenesis. For example, let-7 has been shown to be misregulated in lung cancer, which is thought to behave as tumor suppressor and to repress gene expression of several oncogenes, such as Kras. Furthermore, reduced let-7 level is associated with poor outcomes in lung cancer patients. MiR-145 is a putative tumor suppressing miRNA, which has been shown to negatively regulate multiple oncogenes such as Myc, Kras, IRS-1, and Erk5. Also, miR-145 was reported to suppress cell invasion and metastasis through targeting Muc1 in breast cancers and metastasis suppressor by targeting Fascn1 and Sox2 in prostate cancer and glioma.
Recent reports have demonstrated that tumors contain a small subpopulation of cancer stem cells (CSCs) that possesses self-renewing capacity and is responsible for tumor malignancy including metastasis, relapse, and chemo- and radio- resistance. However, a miRNA-based therapeutic approach in LAC-associated CSCs (LAC-CSCs) is still blurred. Recent studies have shown that miR142-3p inhibits the expression of multiple oncogenes including ras, myc, HMGA2, etc, miR142-3p has been recognized as a tumor suppressor. Moreover, it has been found that miR142-3p could regulate “stemness” by repressing self-renewal and promoting differentiation in both normal development and cancer, suggesting that miR142-3p could regulate cancer stem cell and epithelial-mesenchymal transition (EMT). The aim of our study was to investigate the role of miR145 and miR142-3p in LAC-derived CSC, as well as these miRNA associated pathways in regulating cancer stem cell properties, EMT, and resistance to chemotherapy and radiotherapy. In addition, we explored a non-viral delivery method for miRNAs and further investigated its therapeutic effect as a novel approach for miRNA-based treatment.
In our present study, we found that the expression of miR145 was negatively correlated with the levels of Oct4/Sox2/Fascin1 in LAC patient specimens, and an Oct4(high)Sox2(high)Fascin1(high)miR145(low)phenotype was associated with poor prognosis. We enriched LAC-CSCs by side population sorting or identification of CD133 markers and found that LAC-CSCs exhibit low miR145 and high Oct4/Sox2/Fascin1 expression, CSC-like properties, and chemo- and radio-resistance. The delivery of miR145 reduced CSC-like properties, and improved chemo- and radio- resistance in LAC-CSCs by directly targeting Oct4/Sox2/Fascin1. On the contrary, the delivery of anti-miR145 promoted cancer stem-like and tumor-initiating capability. For miR142-3p, the expression of miR142-3p was significantly decreased in side population (SP)-positive lung cancer cells. The expression of miR142-3p was negatively correlates with the expression levels of HMGA2 and Sox2 in LAC. Also, the expression of profile of Sox2(high)HMGA2(high)miR142-3p(low) is associated with inferior survival of LAC patients.
Together, we demonstrated the inhibitory effects of miR145 on self-renewal, tumor-initiating, chemoradio-resistance, EMT, and metastasis partially, via repressing Oct4/Sox2/Fascin1 in LAC. In addition, miR142-3p may be a prognosis marker and potential therapeutic agent of miRNA-based approach for therapeutic resistant LAC. These studies advance our understanding of miRNA regulation of cancer and provide a novel miRNA-based approach targeting miR145 and miR142-3p for lung cancer treatment.
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