Browsing by Author "Chiu, C-C"

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Resistin facilitates breast cancer progression via TLR4-mediated induction of mesenchymal phenotypes and stemness properties
(2018-02-01)
Wang, C-H
;
Wang, P-J
;
Hsieh, Y-C
;
Lo, S.
;
Lee, Y-C
Growing evidence indicates that resistin-an obesity-related cytokine-is upregulated in breast cancer patients, yet its impact on breast cancer behavior remains to be ascertained. Similarly, Toll-like receptor 4 (TLR4) has been implicated in breast cancer progression, however, its clinically relevant endogenous ligand remains elusive. In this study, we observed that high serum resistin levels in breast cancer patients positively correlated with tumor stage, size and lymph node metastasis. These findings were replicated in animal models of breast cancer tumorigenesis and metastasis. Resistin was found to promote epithelial-mesenchymal transition and stemness in breast cancer cells-mechanisms critical to tumorigenesis and metastasis-through a TLR4/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B)/signal transducer and activator of transcription 3 (STAT3) signaling pathway and negated by TLR4-specific antibody and antagonist. These findings provide clear evidence that resistin is a clinically relevant endogenous ligand for TLR4, which promotes tumor progression via TLR4/NF-kappa B/STAT3 signaling, providing insights into a novel therapeutic target in breast cancer.
YB-1 disrupts mismatch repair complex formation, interferes with MutS alpha recruitment on mismatch and inhibits mismatch repair through interacting with PCNA
(2014-10-23)
Chang, Y-W
;
Mai, R-T
;
Fang, W-H
;
Lin, C-C
;
Chiu, C-C
Y-box binding protein-1 (YB-1) is highly expressed in tumors and it participates in various cellular processes. Previous studies indicated that YB-1 binds to mispaired DNA and interacts with several mismatch repair (MMR)-related factors. However, its role in the MMR system remains undefined. Here, we found that YB-1 represses mutS homolog 6 (MSH6)-containing MMR complex formation and reduces MutS alpha mismatch binding activity by disrupting interactions among MMR-related factors. In an effort to elucidate how YB-1 exerts this inhibitory effect, we have identified two functional proliferating cell nuclear antigen (PCNA)interacting protein (PIP)-boxes that mediate YB-1/PCNA interaction and locate within the C-terminal region of YB-1. This interaction is critical for the regulatory role of YB-1 in repressing MutSa mismatch binding activity, disrupting MutS alpha/PCNA/G/T heteroduplex ternary complex formation and inhibiting in vitro MMR activity. The differential regulation of 3\' and 5\' nick-directed MMR activity by YB-1 was also observed. Moreover, YB-1 overexpression is associated with the alteration of microsatellite pattern and the enhancement of N-methyl-N\'-nitro-N-nitrosoguanidine (MNNG)-induced and spontaneous mutations. Furthermore, upregulation of other PIP-box-containing proteins, such as myeloid cell leukemia-1 (Mcl-1) and inhibitor of growth protein 1b (ING1b), has no impact on MMR complex formation and mutation accumulation, thus revealing the significant effect of YB-1 on regulating the MMR system. In conclusion, our study suggests that YB-1 functions as a PCNA-interacting factor to exert its regulatory role on the MMR process and involves in the induction of genome instability, which may partially account for the oncogenic potential of YB-1.