New mouse xenograft model modulated by tumor-associated fibroblasts for human multi-drug resistance in cancer

Abstract BackgroundChemoresistance is a major cause of treatment failure in pancreatic cancer (PC). It has been demonstrated that epithelial-to-mesenchymal transition (EMT) is closely related to drug resistance in PC; however, the underlying mechanisms are not yet fully understood. Recently found evidence has suggested that nuclear-enriched abundant transcript 1 (NEAT1) is involved in the development of chemoresistance. However, the role and mechanism of NEAT1 in PC gemcitabine resistance remain unknown.MethodsTwo independent gemcitabine-resistant (GR) PC cell lines, PANC-1/GR and SW1990/GR, were established. Transwell assays were used to validate whether GR cells acquired EMT. qRT-PCR and western blot were performed to detect the expression levels of NEAT1, miR-506-3p, and ZEB2 in GR cells. MTT and cell apoptosis assays were conducted to evaluate the sensitivity of GR cells to gemcitabine. Rescue experiments were employed to investigate whether NEAT1 mediates drug resistance of GR cells through modulation of the miR-506-3p/ZEB2/EMT axis. Furthermore, a mouse xenograft model was established to confirm these findings.ResultsGR cells displayed markedly enhanced migration and invasion abilities, decreased expression of E-cadherin, and upregulation of N-cadherin, Vimentin, Snail, ZEB1, and ZEB2. Furthermore, elevated expression of NEAT1 was observed in GR cells. Downregulation of NEAT1 sensitized GR cells to gemcitabine. More importantly, we demonstrated that downregulation of NEAT1 enhanced the sensitivity of GR cells to gemcitabine by reversing the EMT process. NEAT1 regulated ZEB2 expression by sponging miR-506-3p, and the function of NEAT1 in GR cells was dependent on miR-506-3p. These findings were further confirmed in a nude mouse xenograft model.ConclusionsTaken together, downregulation of NEAT1 sensitized the GR PC cells to gemcitabine through modulation of the miR-506-3p/ZEB2/EMT axis. These results provide a new direction for improving the chemotherapeutic effects in PC.

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265: A Constitutively Activated Mutant form of Propsa that Manifests Catalytic Action Increases Cell Invasion in Vitro and Frequency of Pulmonary Metastases in vivo in a Subcutaneous Mouse Xenograft Model

The Journal of Urology ◽

10.1016/s0022-5347(18)30530-5 ◽

2007 ◽

Vol 177 (4S) ◽

pp. 89-89

Author(s):

Sven Wenske ◽

Todd Hricik ◽

Brett S. Carver ◽

Matthew F. O'Brien ◽

Ruslan Korets ◽

...

Keyword(s):

Cell Invasion ◽

Pulmonary Metastases ◽

Xenograft Model ◽

Catalytic Action ◽

Mutant Form ◽

Mouse Xenograft ◽

Mouse Xenograft Model

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Arsenic nano complex induced degradation of YAP sensitized ESCC cancer cells to radiation and chemotherapy

Cell & Bioscience ◽

10.1186/s13578-020-00508-x ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Wei Zhou ◽

Meiyue Liu ◽

Xia Li ◽

Peng Zhang ◽

Jiong Li ◽

...

Keyword(s):

Transcription Factor ◽

Radiation Therapy ◽

Cancer Cells ◽

Solid Tumors ◽

Xenograft Model ◽

Ros Production ◽

Protective Effects ◽

Migration Ability ◽

Mouse Xenograft ◽

Mouse Xenograft Model

Abstract Background Increased reactive oxygen species (ROS) production by arsenic treatment in solid tumors showed to be effective to sensitize cancer cells to chemotherapies. Arsenic nano compounds are known to increase the ROS production in solid tumors. Methods In this study we developed arsenic–ferrosoferric oxide conjugated Nano Complex (As2S2–Fe3O4, AFCNC) to further promote the ROS induction ability of arsenic reagent in solid tumors. We screen for the molecular pathways that are affect by arsenic treatment in ESCC cancer cells. And explored the underlying molecular mechanism for the arsenic mediated degradations of the key transcription factor we identified in the gene microarray screen. Mouse xenograft model were used to further verify the synthetic effects of AFCNC with chemo and radiation therapies, and the molecular target of arsenic treatment is verified with IHC analysis. Results With gene expression microarray analysis we found Hippo signaling pathway is specifically affected by arsenic treatment, and induced ubiquitination mediated degradation of YAP in KYSE-450 esophageal squamous cell carcinoma (ESCC) cells. Mechanistically we proved PML physically interacted with YAP, and arsenic induced degradation PML mediated the degradation of YAP in ESCC cells. As a cancer stem cell related transcription factor, YAP 5SA over expressions in cancer cells are correlated with resistance to chemo and radiation therapies. We found AFCNC treatment inhibited the increased invasion and migration ability of YAP 5SA overexpressing KYSE-450 cells. AFCNC treatment also effectively reversed protective effects of YAP 5SA overexpression against cisplatin induced apoptosis in KYSE-450 cells. Lastly, with ESCC mouse xenograft model we found AFCNC combined with cisplatin treatment or radiation therapy significantly reduced the tumor volumes in vivo in the xenograft ESCC tumors. Conclusions Together, these findings suggested besides ROS, YAP is a potential target for arsenic based therapy in ESCC, which should play an important role in the synthetic effects of arsenic nano complex with chemo and radiation therapy.

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Oncogenic lncRNA ZNF561-AS1 is essential for colorectal cancer proliferation and survival through regulation of miR-26a-3p/miR-128-5p-SRSF6 axis

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01882-1 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Zizhen Si ◽

Lei Yu ◽

Haoyu Jing ◽

Lun Wu ◽

Xidi Wang

Keyword(s):

Colorectal Cancer ◽

Rna Binding ◽

Xenograft Model ◽

Luciferase Reporter ◽

Cancer Proliferation ◽

Mouse Xenograft ◽

Mouse Xenograft Model

Abstract Background Long non-coding RNAs (lncRNA) are reported to influence colorectal cancer (CRC) progression. Currently, the functions of the lncRNA ZNF561 antisense RNA 1 (ZNF561-AS1) in CRC are unknown. Methods ZNF561-AS1 and SRSF6 expression in CRC patient samples and CRC cell lines was evaluated through TCGA database analysis, western blot along with real-time PCR. SRSF6 expression in CRC cells was also examined upon ZNF561-AS1 depletion or overexpression. Interaction between miR-26a-3p, miR-128-5p, ZNF561-AS1, and SRSF6 was examined by dual luciferase reporter assay, as well as RNA binding protein immunoprecipitation (RIP) assay. Small interfering RNA (siRNA) mediated knockdown experiments were performed to assess the role of ZNF561-AS1 and SRSF6 in the proliferative actives and apoptosis rate of CRC cells. A mouse xenograft model was employed to assess tumor growth upon ZNF561-AS1 knockdown and SRSF6 rescue. Results We find that ZNF561-AS1 and SRSF6 were upregulated in CRC patient tissues. ZNF561-AS1 expression was reduced in tissues from treated CRC patients but upregulated in CRC tissues from relapsed patients. SRSF6 expression was suppressed and enhanced by ZNF561-AS1 depletion and overexpression, respectively. Mechanistically, ZNF561-AS1 regulated SRSF6 expression by sponging miR-26a-3p and miR-128-5p. ZNF561-AS1-miR-26a-3p/miR-128-5p-SRSF6 axis was required for CRC proliferation and survival. ZNF561-AS1 knockdown suppressed CRC cell proliferation and triggered apoptosis. ZNF561-AS1 depletion suppressed the growth of tumors in a model of a nude mouse xenograft. Similar observations were made upon SRSF6 depletion. SRSF6 overexpression reversed the inhibitory activities of ZNF561-AS1 in vivo, as well as in vitro. Conclusion In summary, we find that ZNF561-AS1 promotes CRC progression via the miR-26a-3p/miR-128-5p-SRSF6 axis. This study reveals new perspectives into the role of ZNF561-AS1 in CRC.

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