Tumor Biology

, Volume 37, Issue 9, pp 12315–12327 | Cite as

Integrinβ1 modulates tumour resistance to gemcitabine and serves as an independent prognostic factor in pancreatic adenocarcinomas

  • Dejun Yang
  • Jian Shi
  • Hongbing Fu
  • Ziran Wei
  • Jiapeng Xu
  • Zunqi Hu
  • Yu Zhang
  • Ronglin YanEmail author
  • Qingping CaiEmail author
Original Article


Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies because of its broad resistance to chemotherapy. Numerous evidence indicates that integrinβ1 is upregulated in some human cancers, and it is correlated with resistance to various therapies. However, the role of integrinβ1 in chemotherapy is not clear in pancreatic cancer. The present study evaluates the potential of integrinβ1 to predict chemoresistance and prognosis in patients and to modulate resistance to gemcitabine in PDAC cells. Primary drug-resistance (DR) cancer cells were isolated, and DR cells from MiaPaCa-2 and AsPC-1 parent cell lines (PCL) were selected. Integrinβ1 expression was determined using immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) and Western blotting. Changes in drug response after knockdown of integrinβ1 via RNA interference (RNAi) were evaluated using the viability of cancer cells as colon formation, proliferation using Western blot of Ki-67 and apoptosis using cleaved caspase-3 immunofluorescence. qRT-PCR and Western blot also detected variations in the activities of cdc42 and AKT after integrinβ1 suppression. Patient survival and relative factors were assessed using Kaplan-Meier and Cox regression analyses. Integrinβ1 expression was upregulated in PDAC, which was significantly associated with intrinsic and acquired gemcitabine resistance and worse outcomes. The downregulation of integrinβ1 attenuated PDAC chemoresistance, and this attenuation partially correlated with reduced Cdc42 and AKT activity, which are target molecules of integrinβ1 in some human cancers. These findings identified integrinβ1 as a special marker of drug resistance and a serious prognosis, and they furthermore support the use of integrinβ1 as a novel potential therapeutic target to overcome chemotherapy resistance. The results also suggest a possible drug-resistant signalling pathway of integrinβ1 in PDAC.


Pancreatic ductal adenocarcinoma Integrinβ1 Chemoresistance Survival 



The study was supported by Department of Cell Biology, Basic Research Institute, Second Military Medical University (Shanghai, China).

Authors’ contributions

Qingping Cai conceived and designed the experiments. Dejun Yang and Ronglin Ran revised the manuscript and carried out the further experiments. Dejun Yang, Jian Shi, Hongbing Fu, Ziran Wei, Jiapeng Xu and Yu Zhang performed the experiments. Hongbing Fu and Yu Zhang collected the samples and analysed the data. Dejun Yang wrote the paper. All authors are in agreement with the content of the manuscript and this submission. All authors read and approved the final manuscript.

Compliance with ethical standards

Informed consent was obtained from patients, and the study was approved by the Second Military Medical University Research Ethics Committee (Institutional Review Board), Shanghai, China.

Conflicts of interests



  1. 1.
    Stathis A, Moore MJ. Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol. 2010;7(3):163–72.CrossRefPubMedGoogle Scholar
  2. 2.
    Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010;304(10):1073–81.CrossRefPubMedGoogle Scholar
  3. 3.
    Oettle H, Neuhaus P. Adjuvant therapy in pancreatic cancer: a critical appraisal. Drugs. 2007;67(16):2293–310.CrossRefPubMedGoogle Scholar
  4. 4.
    Neoptolemos JP, Cunningham D, Friess H, Bassi C, Stocken DD, Tait DM, et al. Adjuvant therapy in pancreatic cancer: historical and current perspectives. Ann Oncol. 2003;14(5):675–92.CrossRefPubMedGoogle Scholar
  5. 5.
    Michl P, Gress TM. Current concepts and novel targets in advanced pancreatic cancer. Gut. 2013;62(2):317–26.CrossRefPubMedGoogle Scholar
  6. 6.
    Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362(17):1605–17.CrossRefPubMedGoogle Scholar
  7. 7.
    Tang SC, Chen YC. Novel therapeutic targets for pancreatic cancer. World J Gastroenterol. 2014;20(31):10825–44.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Stewart DJ. Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer. Crit Rev Oncol Hematol. 2010;75(3):173–234.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Oxnard GR, Arcila ME, Chmielecki J, Ladanyi M, Miller VA, Pao W. New strategies in overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer. Clin Cancer Res. 2011;17(17):5530–7.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Zhang L, Wu Z, Zhou Q. Epithelial-mesenchymal transition and tumor chemoresistance. Chin J Lung Canc. 2013;16(1):54–7.Google Scholar
  11. 11.
    Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The pancreas cancer microenvironment. Clin Cancer Res. 2012;18(16):4266–76.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457–61.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Jin H, Su J, Garmy-Susini B, Kleeman J, Varner J. Integrin alpha4beta1 promotes monocyte trafficking and angiogenesis in tumors. Cancer Res. 2006;66(4):2146–52.CrossRefPubMedGoogle Scholar
  14. 14.
    Weaver VM, Lelièvre S, Lakins JN, Chrenek MA, Jones JC, Giancotti F, et al. Beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. Cancer Cell. 2002;2(3):205–16.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Guo W, Giancotti FG. Integrin signalling during tumour progression. Nat Rev Mol Cell Biol. 2004;5(10):816–26.CrossRefPubMedGoogle Scholar
  16. 16.
    Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15(3):220–31.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Li N, Zhang Y, Naylor MJ, Schatzmann F, Maurer F, Wintermantel T, et al. Beta1 integrins regulate mammary gland proliferation and maintain the integrity of mammary alveoli. EMBO J. 2005;24(11):1942–53.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Friedl P, Wolf K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer. 2003;3(5):362–74.CrossRefPubMedGoogle Scholar
  19. 19.
    Jahangiri A, Aghi MK, Carbonell WS. β1 integrin: critical path to antiangiogenic therapy resistance and beyond. Cancer Res. 2014;74(1):3–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Huang C, Park CC, Hilsenbeck SG, Ward R, Rimawi MF, Wang YC, et al. Beta1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib. Breast Cancer Res. 2011;13(4):R84.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Nam JM, Chung Y, Hsu HC, Park CC. Beta1 integrin targeting to enhance radiation therapy. Int J Radiat Biol. 2009;85(11):923–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Mocanu MM, Fazekas Z, Petras M, Nagy P, Sebestyen Z, Isola J, et al. Associations of ErbB2, beta1-integrin, and lipid rafts on Herceptin (Trastuzumab) resistant and sensitive tumor cell lines. Cancer Lett. 2005;227(2):201–12.CrossRefPubMedGoogle Scholar
  23. 23.
    Kleeff J, Beckhove P, Esposito I, Herzig S, Huber PE, Löhr JM, et al. Pancreatic cancer microenvironment. Int J Cancer. 2007;121(4):699–705.CrossRefPubMedGoogle Scholar
  24. 24.
    Erkan M, Hausmann S, Michalski CW, Fingerle AA, Dobritz M, Kleeff J, et al. The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol. 2012;9(8):454–67.CrossRefPubMedGoogle Scholar
  25. 25.
    Ugurel S, Schadendorf D, Pföhler C, Neuber K, Thoelke A, Ulrich J, et al. In vitro drug sensitivity predicts response and survival after individualized sensitivity-directed chemotherapy in metastatic melanoma: a multicenter phase II trial of the Dermatologic Cooperative Oncology Group. Clin Cancer Res. 2006;12(18):5454–63.CrossRefPubMedGoogle Scholar
  26. 26.
    Michalski CW, Erkan M, Sauliunaite D, Giese T, Stratmann R, Sartori C, et al. Ex vivo chemosensitivity testing and gene expression profiling predict response towards adjuvant gemcitabine treatment in pancreatic cancer. Br J Cancer. 2008;99(5):760–7.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Hamed SS, Straubinger RM, Jusko WJ. Pharmacodynamic modeling of cell cycle and apoptotic effects of gemcitabine on pancreatic adenocarcinoma cells. Cancer Chemother Pharmacol. 2013;72(3):553–63.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Park CC, Bissell MJ, Barcellos-Hoff MH. The influence of the microenvironment on the malignant phenotype. Mol Med Today. 2000;6(8):324–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Goodman SL, Picard M. Integrins as therapeutic targets. Trends Pharmacol Sci. 2012;33(7):405–12.CrossRefPubMedGoogle Scholar
  30. 30.
    Uhm JH, Gladson CL, Rao JS. The role of integrins in the malignant phenotype of gliomas. Front Biosci. 1999;4:D188–99.CrossRefPubMedGoogle Scholar
  31. 31.
    Costello BA, Borad MJ, Qi Y, Kim GP, Northfelt DW, Erlichman C, et al. Phase I trial of everolimus, gemcitabine and cisplatin in patients with solid tumors. Invest New Drugs. 2014;32(4):710–6.CrossRefPubMedGoogle Scholar
  32. 32.
    Dutertre M, Sanchez G, Barbier J, Corcos L, Auboeuf D. The emerging role of pre-messenger RNA splicing in stress responses: sending alternative messages and silent messengers. RNA Biol. 2011;8(5):740–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Busà R, Geremia R, Sette C. Genotoxic stress causes the accumulation of the splicing regulator Sam68 in nuclear foci of transcriptionally active chromatin. Nucleic Acids Res. 2010;38(9):3005–18.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kutys ML, Yamada KM. An extracellular-matrix-specific GEF-GAP interaction regulates Rho GTPase crosstalk for 3D collagen migration. Nat Cell Biol. 2014;16(9):909–17.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Stengel K, Zheng Y. Cdc42 in oncogenic transformation, invasion, and tumorigenesis. Cell Signal. 2011;23(9):1415–23.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Reymond N, Im JH, Garg R, Vega FM, Borda d’Agua B, Riou P, et al. Cdc42 promotes transendothelial migration of cancer cells through β1 integrin. J Cell Biol. 2012;199(4):653–68.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489–501.CrossRefPubMedGoogle Scholar
  38. 38.
    Miao H, Li S, Hu YL, Yuan S, Zhao Y, Chen BP, et al. Differential regulation of Rho GTPases by β1 and β3 integrins: the role of an extracellular domain of integrin in intracellular signaling. J Cell Sci. 2002;115(Pt10):2199–206.PubMedGoogle Scholar
  39. 39.
    Kanda R, Kawahara A, Watari K, Murakami Y, Sonoda K, Maeda M, et al. Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling. Cancer Res. 2013;73(20):6243–53.CrossRefPubMedGoogle Scholar
  40. 40.
    Dastpeyman M, Motamed N, Azadmanesh K, Mostafavi E, Kia V, Jahanian-Najafabadi A, et al. Inhibition of silibinin on migration and adhesion capacity of human highly metastatic breast cancer cell line, MDA-MB-231, by evaluation of β1-integrin and downstream molecules, Cdc42, Raf-1 and D4GDI. Med Oncol. 2012;29(4):2512–8.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Dejun Yang
    • 1
  • Jian Shi
    • 2
  • Hongbing Fu
    • 1
  • Ziran Wei
    • 1
  • Jiapeng Xu
    • 1
  • Zunqi Hu
    • 1
  • Yu Zhang
    • 1
  • Ronglin Yan
    • 1
    Email author
  • Qingping Cai
    • 1
    Email author
  1. 1.Department of Gastrointestinal Surgery, Changzheng HospitalSecond Military Medical UniversityShanghaiChina
  2. 2.Department of Gastroenterology, Changzheng HospitalSecond Military Medical UniversityShanghaiChina

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