Notch 3 Protein, not its Gene Polymorphism, is Associated with the Chemotherapy Response and Prognosis of Advanced NSCLC Patients

Background/Aims: Tropomyosin-2 (TPM2) plays important roles in functions of the cytoskeleton, such as cytokinesis, vesicle transport, cell proliferation, migration and apoptosis,and these functions imply that TPM2 also plays a role in cancer development. Indeed, it has been shown that TPM2 plays a critical role in some cancers. However, the role of TPM2 in breast cancer is still poorly characterized. Thus, we explored the role of TPM2 in breast cancer. Methods: We analysed TPM2 expression and its correlation with the clinicopathological features in breast cancer. Then, we examined the influence of hypoxia on TPM2 expression and methylation status using bisulfite sequencing PCR. Furthermore, we performed TPM2-mediated migration and invasion assays in the context of hypoxia and examined changes in matrix metalloproteinase-2 (MMP2) expression. Finally, we detected the influence of TPM2 on survival and chemotherapy drug sensitivity. Results: We found that TPM2 expression is down-regulated in breast cancer cells compared to that in normal breast cells. The data from TCGA supported these results. Promoter methylation of TPM2, which could be induced by hypoxia, was responsible for its low expression. Hypoxia might regulate cell invasiveness partly by TPM2 down-regulation-mediated changes of MMP2 expression. Importantly, low TPM2 expression was correlated with lymph node metastasis (P=0.031), tumour node metastasis stage (P=0.01), histological grade (P=0.037), and shorter overall survival (P=0.028). Univariate and multivariate analyses indicated that TPM2 was an independent predictor in breast cancer patients. Paclitaxel chemotherapy did not benefit patients with low TPM2 expression (P<0.0001). TPM2 knockdown significantly reduced cell sensitivity to paclitaxel. Conclusion: TPM2 is a potential novel tumour suppressor gene in breast cancer. TPM2 is associated with poor survival and chemoresistance to paclitaxel in breast cancer, and TPM2 may represent a promising therapeutic gene target for breast cancer patients with chemoresistance.

Section: Introductionmentioning

confidence: 99%

Hypoxia-Induced TPM2 Methylation is Associated with Chemoresistance and Poor Prognosis in Breast Cancer

Zhang

et al. 2018

“…It has been reported that genetic Variants and protein expressions might affect the platinum-based chemotherapy response and prognosis of advanced NSCLC patients [36,37]. Platinum-based chemotherapy as a main treatment for lung cancer exerts its anti-cancer effect largely through the formation of bulky platinum-DNA adducts, which result in destabilization of the DNA double helix that otherwise blocks replication and inhibits transcription.…”

Section: Discussionmentioning

confidence: 99%

DNA Repair Gene Polymorphisms in Relation to Non-Small Cell Lung Cancer Survival

Zhang

et al. 2015

Key WordsAbstract Background: Single nucleotide polymorphisms (SNPs) in the DNA repair genes are suspected to be related to the survival of lung cancer patients due to their possible influence on DNA repair capacity (DRC). However, the study results are inconsistent. Methods: A follow-up study of 610 non-small cell lung cancer (NSCLC) patients was conducted to investigate genetic polymorphisms associated with the DNA repair genes in relation to NSCLC survival; 6 SNPs were genotyped, including XRCC1

“…As a classical Notch signaling pathway, the CBF-1/RBP-Jk pathway plays a pivotal role in mammals [38]. Studies have shown that adjacent cells transfer Notch signals to each other via the binding of receptors and ligands through a signaling cascade to regulate cellular behavior, including, proliferation, development, organ formation and morphogenesis [38,39]. In general, the ligand such as JAGGED, which can be combined with membrane receptor NOTCH1 to conduct signals, eventually activates the expression of the primary target genes Hes1 and Hes5; the latter was shown to regulate cell proliferation and differentiation [40,41].…”

Section: Discussionmentioning

confidence: 99%

The Expression of Markers Related to Ovarian Germline Stem Cells in the Mouse Ovarian Surface Epithelium and the Correlation with Notch Signaling Pathway

Pan

Sun

et al. 2015

Background/Aims: Ovarian germline stem cells (OGSCs) have been shown to mainly exist in the ovarian surface epithelium (OSE), but the activity changes of germline stem cells during different reproductive stages and the potential regulatory signaling pathway are still unknown. The Notch signaling pathway plays a key role in cell development, primordial follicles and stem cell proliferation. However, whether it plays a role in the proliferation of OGSCs is unknown. Here, we analyzed the activity changes of germline stem cells and the correlation between germline stem cells and the Notch signaling pathway. Methods: The expression of germline stem cell markers Mvh, Ooc4 and the Notch molecules Notch1, Hes1, and Hes5 were detected during 3 days (3d), and 2, 12, 20 months (2m, 12m, 20m) mouse ovarian surface epithelium samples. DAPT, a specific inhibitor of the Notch pathway, was used to observe the influence of Notch signaling in the germline stem cells. Results: The results showed that the levels of MVH and OCT4 decreased substantially with reproductive age in ovarian surface epithelium, and the same tendency was detected in the Notch signaling molecules Notch1, Hes1 and Hes5. Dual-IF results showed that the germline stem cell markers were co-expressed with Notch molecules in the ovarian surface epithelium. While, the expression of MVH and OCT4 were reduced when the ovaries were treated with DAPT and the levels were attenuated with increasing dose of DAPT. Conclusion: Taken together, our results indicate that the viability of OGSCs decreased with the age of the mouse ovaries, and the activity of OGSCs in the ovarian surface epithelium may be related to the Notch signaling pathway.