Integrated analysis of gene expression and methylation profiles of novel pancreatic cancer cell lines with highly metastatic activity
Pancreatic cancer is one of the most lethal human malignancies, partly because of its propensity for metastasis. However, highly metastatic human pancreatic cancer cell lines suitable for studies of metastasis are currently lacking. Here we established two highly metastatic human pancreatic cancer cell lines, MIA PaCa-2 In8 and Panc-1 In8, by Matrigel induction assay. The cell lines were further characterized both in vitro and in vivo. MIA PaCa-2 In8 and Panc-1 In8 cells demonstrated increased migration and invasion compared with their respective parental cells. Following injection into nude mice, MIA PaCa-2 In8 and Panc-1 In8 cells resulted in more pulmonary metastases compared with the parental cells. Furthermore, analyses of mRNA, long non-coding RNA, micro RNA, and methylation profiling revealed that these factors were aberrantly regulated in the highly metastatic cells, indicating that they probably affected metastasis. We thus established and characterized two highly metastatic human pancreatic cell lines that could be used as valuable tools for future investigations into the pathogenesis, metastasis, and potential treatment of human pancreatic cancer.
Keywordspancreatic cancer high metastatic activity gene expression methylation
This work was supported by the CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-12M-3-005 and 2016-I2M-1-001), PUMC Youth Fund and the Fundamental Research Funds for the Central Universities (2017320027), the National Natural Science Foundation of China (81772639), and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2018PT32014).
- Go, K.L., Delitto, D., Judge, S.M., Gerber, M.H., George Jr, T.J., Behrns, K.E., Hughes, S.J., Judge, A.R., and Trevino, J.G. (2017). Orthotopic patient-derived pancreatic cancer xenografts engraft into the pancreatic parenchyma, metastasize, and induce muscle wasting to recapitulate the human disease. Pancreas 46, 813–819.CrossRefGoogle Scholar
- Haskins, J.W., Nguyen, D.X., and Stern, D.F. (2014). Neuregulin 1-activated ERBB4 interacts with YAP to induce Hippo pathway target genes and promote cell migration. Sci Signal 7, ra116.Google Scholar
- Karreth, F.A., and Pandolfi, P.P. (2013). ceRNA cross-talk in cancer: when ce-bling rivalries go awry. Cancer Discov 3, 1113–1121.Google Scholar
- McDonald, O.G., Li, X., Saunders, T., Tryggvadottir, R., Mentch, S.J., Warmoes, M.O., Word, A.E., Carrer, A., Salz, T.H., Natsume, S., et al. (2017). Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat Genet 49, 367–376.CrossRefGoogle Scholar
- Reticker-Flynn, N.E., Malta, D.F.B., Winslow, M.M., Lamar, J.M., Xu, M. J., Underhill, G.H., Hynes, R.O., Jacks, T.E., and Bhatia, S.N. (2012). A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis. Nat Commun 3, 1122.CrossRefGoogle Scholar
- Salameh, A., Lee, A.K., Cardó-Vila, M., Nunes, D.N., Efstathiou, E., Staquicini, F.I., Dobroff, A.S., Marchiò, S., Navone, N.M., Hosoya, H., et al. (2015). PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3. Proc Natl Acad Sci USA 112, 8403–8408.CrossRefGoogle Scholar
- Tahira, A.C., Kubrusly, M.S., Faria, M.F., Dazzani, B., Fonseca, R.S., Maracaja-Coutinho, V., Verjovski-Almeida, S., Machado, M.C.C., and Reis, E.M. (2011). Long noncoding intronic RNAs are differentially expressed in primary and metastatic pancreatic cancer. Mol Cancer 10, 141.CrossRefGoogle Scholar
- Wang, C., Zhang, W., Zhang, L., Chen, X., Liu, F., Zhang, J., Guan, S., Sun, Y., Chen, P., Wang, D., et al. (2016). miR-146a-5p mediates epithelial–mesenchymal transition of oesophageal squamous cell carcinoma via targeting Notch2. Br J Cancer 115, 1548–1554.Google Scholar
- Yang, Q., Wang, Y., Lu, X., Zhao, Z., Zhu, L., Chen, S., Wu, Q., Chen, C., and Wang, Z. (2015). MiR-125b regulates epithelial-mesenchymal transition via targeting Sema4C in paclitaxel-resistant breast cancer cells. Oncotarget 6, 3268–3279.Google Scholar
- Zhang, J.Y., Weng, M.Z., Song, F.B., Xu, Y.G., Liu, Q., Wu, J.Y., Qin, J., Jin, T., and Xu, J.M. (2016). Long noncoding RNA AFAP1-AS1 indicates a poor prognosis of hepatocellular carcinoma and promotes cell proliferation and invasion via upregulation of the RhoA/Rac2 signaling. Int J Oncol 48, 1590–1598.CrossRefGoogle Scholar