| Summary: | 博士 === 國立中央大學 === 生命科學系 === 104 === The family of suppressors of cytokine signaling (SOCS) consists of eight members, including SOCS1–7 and CIS. The main structure of SOCS includes a variant region at the N-terminus, SH2 domain, and SOCS box. The SH2 domain and SOCS box are the essential regions for regulating the signaling pathway, with the negative feedback inhibition of janus kinase/signal transducer and activator of transcription (JAK/STAT). In recent years, SOCS family members have been found to play important roles in cancer. However, many functions and mechanisms still need further identification and validation. In the first part of the study, we found that the SOCS2 expression level was lower in 40 patients with oral cancer, and this is consistent with the current findings that SOCS2 expression is inhibited in many malignant solid tumors. Recently, the role of microRNA (miRNA) in cancers development has attracted more attention. Thus, we attempted to investigate the role of miRNA in inhibiting SOCS2 in oral cancer. Using targeting algorithms (miRNAmap and microRNA.org) combined with OSCC patients' miRNA microarray data, we wanted to search for putative miRNAs that might bind to SOCS2 mRNA. Based on the computational screening, we identified one miRNA, miR-424-5p, which was significantly upregulated in OSCC tumors compared with their corresponding normal samples (p < 0.0001). We later proved that the inhibition of miR-424-5p expression in oral cancer cells increased SOCS2 expression and inhibits STAT5 activity. It was also shown that interleukin-8 (IL-8) increases miR-424-5p expression, further inhibited SOCS2 expression, and activated STAT5 signaling pathway. Interestingly, IL-8 induces miR-424-5p expression, resulting in the proliferation and invasion of oral cancer cells via activating STAT5. From these results, a new mechanism was established, i.e., miR-424-5p mediates the progression of oral cancer by functionally connecting the signaling pathway among IL-8, miR-424-5p, SOCS2, and STAT5. In the second part of the study, the effect of a novel microtubule inhibitor, MPT0B098, on oral cancer cells was investigated. MPT0B098 is a newly synthesized sulfonamide-type small-molecule compound that was designed based on the structure of ABT-751, which was at Phase II clinical trial from Abbott. The results showed that MPT0B098 inhibited the growth of oral cancer cell lines and induced apoptosis in oral cancer cells. It was found that MPT0B098 inhibited JAK/STAT3 signaling via increasing the protein level of SOCS3 in oral cancer cells. The relationship between microtubule and SOCS3 is currently unknown, and our study showed that microtubule is closely related to SOCS3. Therefore, SOCS3 could be a potential treatment target for MPT0B098 treatment. The effect of inhibiting cancer cell lines by combining MPT0B098 with either cisplatin or 5-fluorouracil (FU) was found to be better than that by combining cisplatin and 5-FU. In these studies, we hope to show that this microtubule inhibitor, MPT0B098, could be a promising treatment for cancers. This thesis found that the SOCS family plays a pivotal role in oral cancer. We also found a new possible SOCS regulation pathway in these two studies that can help us to understand the effects of other factors (drug or miRNA) on SOCS cell signaling-related reactions, including migration, invasion and cell proliferation.
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