Abstract 6072: MUC16-Cter cleavage increases the metastatic potential in pancreatic cancer
Autor: | Saravanakumar Marimuthu, Imayavaramban Lakshmanan, Sakthivel Muniyan, Maneesh Jain, Surinder K. Batra, Moorthy P. Ponnusamy, Pranita Atri |
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Rok vydání: | 2020 |
Předmět: | |
Zdroj: | Cancer Research. 80:6072-6072 |
ISSN: | 1538-7445 0008-5472 |
Popis: | Pancreatic cancer (PC) is one of the most lethal malignant tumors. Several membrane-bound mucins are overexpressed in PC, including MUC16. The role and molecular mechanism of MUC16 mucin, particularly carboxyl-terminal domain (MUC16-Cter) in metastasis of pancreatic cancer, are poorly understood. Therefore, we hypothesize that the “MUC16-Cter domain plays a vital role in facilitating metastasis in pancreatic cancer”. Here, we knockout MUC16 in Capan 1 PC cells and overexpressed MUC16-Cter (F114AA) domain in MiaPaCa2 PC cells to study its functional impact in PC. Capan-1 MUC16 knockout cells displayed a significant decrease in colony-forming by in vitro tumorigenicity assay, endothelial binding, and P-selectin binding ability compared to control cells. Whereas, MUC16-Cter domain overexpressed MiaPaCa2 cells showed a significant increase in colony formation as compared to vector control cells. These results suggest that MUC16 plays a role in promoting in vitro tumorigenicity and facilitating intravasation and circulation of PC cell by interacting with endothelial cells during the metastatic spread of PC cells. Interestingly, we observed that chemotherapeutic drug (gemcitabine) induces MUC16-Cter cleavage in PC cells. We generated a genetically engineered mouse model Muc16-/- with KrasG12D, Trp53R172H/+, Pdx1-Cre (KPCM) background to study the role of Muc16 in PC tumorigenesis and metastasis with existing KPC model. KPCM showed decreased the early onset of cancer formation compared to KPC. Further, the Kaplan Meier test showed an increased survival rate in Muc16 -/- with KPC background as compared to KPC mice. EMT markers showed decreased expression in KPCM compared to KPC tumors. KPCM cells showed a significant decreased in migratory potential, endothelial, and P-selectin binding ability KPC PC cells. In conclusion, our in vitro and in vivo findings confirm that MUC16 and its Cter domain might play an essential role during the PC tumorigenesis and metastasis. Therefore, targeting MUC16-Cter might be an ideal therapeutic strategy for inhibiting tumorigenesis and metastasis of PC. Citation Format: Saravanakumar Marimuthu, Imayavaramban Lakshmanan, Sakthivel Muniyan, Pranita Atri, Maneesh Jain, Moorthy P. Ponnusamy, Surinder K. Batra. MUC16-Cter cleavage increases the metastatic potential in pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6072. |
Databáze: | OpenAIRE |
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