Advertisement

Medical Oncology

, 32:358 | Cite as

Clinical implication of Sox9 and activated Akt expression in pancreatic ductal adenocarcinoma

  • Suhua Xia
  • Zhenyu Feng
  • Xiaowei Qi
  • Yuan Yin
  • Jianqiang Jin
  • Yufeng Wu
  • Haorong Wu
  • Yizhong Feng
  • Min Tao
Original Paper

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most leading causes of cancer-related death. Cancer stem cell is responsible for tumor initiation, metastasis and relapse. Sox9 is a pancreatic stem cell marker. PI3K/PTEN/Akt/mTORC is an important signal for maintaining stem cells. The purpose of this study is to determine the expression pattern of Sox9 and p-Akt in human PDAC and its correlation with prognosis. Immunohistochemical analysis was used to explore the expression of Sox9 and p-Akt in 88 human PDAC patients. The Pearson’s test was used to compare the clinicopathological parameters between negative and positive expressors. The Pearson’s correlation analysis was used to explore the relationship between Sox9 and p-Akt expression. Kaplan–Meier’s method and Cox regression analysis were used to analyze patients’ survival. The results showed that Sox9 and p-Akt overactivated in PDAC (p = 0.011, p = 0.008). Sox9-positive expression is significantly associated with distant metastasis (p = 0.046). p-Akt-positive expression is significantly associated with distant metastasis (p = 0.000), TNM stage (0.001) and PCNA expression (p = 0.000). Sox9 expression is positively correlated with p-Akt expression (r = 0.314, p = 0.003). In 54 patients with survival information, both Sox9- and p-Akt-positive expressions are associated with unfavorable prognosis (p = 0.002, p = 0.000). Sox9 and p-Akt double-positive expressor showed much poorer prognosis (p = 0.000). Cox regression analysis showed that Sox9- or p-Akt-positive expression and LN metastasis were independent prognostic factors. This study provides the first evidence that Sox9 and p-Akt are both relevant to distant metastasis and proliferation. Our data suggest the potential of Sox9 and p-Akt as prognostic biomarkers for PDAC.

Keywords

Pancreatic ductal adenocarcinoma Sox9 p-Akt Prognosis 

Notes

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (Nos. 81101867, 81272542, 81200369 and 81372443), the China International Medical Foundation (CIMF-F-H001-057), the Scientific Research Project of Jiangsu Provincial Bureau of Traditional Chinese Medicine (L213236), the Medical Scientific Research Project of Jiangsu Provincial Bureau of Health (Z201206), the Special Foundation of Wu Jieping Medical Foundation for Clinical Scientific Research (Nos. 320.6753.1225 and 320.6750.12242), the Science and Education for Health Foundation of Suzhou for Youth (Nos. SWKQ1003 and SWKQ1011), the Scientific Research and Innovation Plan Project of Jiangsu Province for Postgraduate (CXLX13_838) and the Science and Technology Project Foundation of Suzhou (Nos. SYS201112, SYSD2012137 and SYS201335).

Conflict of interest

We declare that we have no conflict of interest.

References

  1. 1.
    Pritchett J, Athwal V, Roberts N, Hanley NA, Hanley KP. Understanding the role of SOX9 in acquired diseases: lessons from development. Trends Mol Med. 2011;17(3):166–74. doi: 10.1016/j.molmed.2010.12.001.PubMedCrossRefGoogle Scholar
  2. 2.
    Wagner T, Wirth J, Meyer J, Zabel B, Held M, Zimmer J, et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell. 1994;79(6):1111–20.PubMedCrossRefGoogle Scholar
  3. 3.
    Kawaguchi Y. Sox9 and programming of liver and pancreatic progenitors. J Clin Investig. 2013;123(5):1881–6. doi: 10.1172/jci66022.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Piper K, Ball SG, Keeling JW, Mansoor S, Wilson DI, Hanley NA. Novel SOX9 expression during human pancreas development correlates to abnormalities in Campomelic dysplasia. Mech Dev. 2002;116(1–2):223–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S, Kuhara T, et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet. 2011;43(1):34–41. doi: 10.1038/ng.722.PubMedCrossRefGoogle Scholar
  6. 6.
    Seymour PA, Freude KK, Tran MN, Mayes EE, Jensen J, Kist R, et al. SOX9 is required for maintenance of the pancreatic progenitor cell pool. Proc Natl Acad Sci USA. 2007;104(6):1865–70. doi: 10.1073/pnas.0609217104.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Matheu A, Collado M, Wise C, Manterola L, Cekaite L, Tye AJ, et al. Oncogenicity of the developmental transcription factor Sox9. Cancer Res. 2012;72(5):1301–15. doi: 10.1158/0008-5472.can-11-3660.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Wang L, He S, Yuan J, Mao X, Cao Y, Zong J, et al. Oncogenic role of SOX9 expression in human malignant glioma. Med Oncol. 2012;29(5):3484–90. doi: 10.1007/s12032-012-0267-z.PubMedCrossRefGoogle Scholar
  9. 9.
    Sun L, Mathews LA, Cabarcas SM, Zhang X, Yang A, Zhang Y, et al. Epigenetic regulation of SOX9 by the NF-kappaB signaling pathway in pancreatic cancer stem cells. Stem Cells. 2013;31(8):1454–66. doi: 10.1002/stem.1394.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489–501. doi: 10.1038/nrc839.PubMedCrossRefGoogle Scholar
  11. 11.
    Kumar A, Rajendran V, Sethumadhavan R, Purohit R. AKT kinase pathway: a leading target in cancer research. Sci World J. 2013;2013:756134. doi: 10.1155/2013/756134.Google Scholar
  12. 12.
    Hollander MC, Blumenthal GM, Dennis PA. PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer. 2011;11(4):289–301. doi: 10.1038/nrc3037.PubMedCrossRefGoogle Scholar
  13. 13.
    Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer. 2009;9(7):463–75. doi: 10.1038/nrc2656.PubMedCrossRefGoogle Scholar
  14. 14.
    Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9(8):550–62. doi: 10.1038/nrc2664.PubMedCrossRefGoogle Scholar
  15. 15.
    Chadha KS, Khoury T, Yu J, Black JD, Gibbs JF, Kuvshinoff BW, et al. Activated Akt and Erk expression and survival after surgery in pancreatic carcinoma. Ann Surg Oncol. 2006;13(7):933–9. doi: 10.1245/aso.2006.07.011.PubMedCrossRefGoogle Scholar
  16. 16.
    Liu J, Sun SHC, Sun SJ, Huang C, Hu HH, Jin YB, et al. Phosph-Akt1 expression is associated with a favourable prognosis in pancreatic cancer. Ann Acad Med Singap. 2010;39(7):548.PubMedGoogle Scholar
  17. 17.
    Yamamoto S, Tomita Y, Hoshida Y, Morooka T, Nagano H, Dono K, et al. Prognostic significance of activated Akt expression in pancreatic ductal adenocarcinoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2004;10(8):2846–50.CrossRefGoogle Scholar
  18. 18.
    Wang Z, Li Y, Ahmad A, Banerjee S, Azmi AS, Kong D, et al. Pancreatic cancer: understanding and overcoming chemoresistance. Nat Rev Gastroenterol Hepatol. 2011;8(1):27–33. doi: 10.1038/nrgastro.2010.188.PubMedCrossRefGoogle Scholar
  19. 19.
    Moghbeli M, Moghbeli F, Forghanifard MM, Abbaszadegan MR. Cancer stem cell detection and isolation. Med Oncol. 2014;31(9):69. doi: 10.1007/s12032-014-0069-6.PubMedCrossRefGoogle Scholar
  20. 20.
    Wang YH, Li F, Luo B, Wang XH, Sun HC, Liu S, et al. A side population of cells from a human pancreatic carcinoma cell line harbors cancer stem cell characteristics. Neoplasma. 2009;56(5):371–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Badea L, Herlea V, Dima SO, Dumitrascu T, Popescu I. Combined gene expression analysis of whole-tissue and microdissected pancreatic ductal adenocarcinoma identifies genes specifically overexpressed in tumor epithelia. Hepatogastroenterology. 2008;55(88):2016–27.PubMedGoogle Scholar
  22. 22.
    Logsdon CD, Simeone DM, Binkley C, Arumugam T, Greenson JK, Giordano TJ, et al. Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer. Cancer Res. 2003;63(10):2649–57.PubMedGoogle Scholar
  23. 23.
    Pei H, Li L, Fridley BL, Jenkins GD, Kalari KR, Lingle W, et al. FKBP51 affects cancer cell response to chemotherapy by negatively regulating Akt. Cancer Cell. 2009;16(3):259–66. doi: 10.1016/j.ccr.2009.07.016.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Kopp JL, von Figura G, Mayes E, Liu FF, Dubois CL, Morris JP, et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;22(6):737–50. doi: 10.1016/j.ccr.2012.10.025.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Meng F, Takaori K, Ito T, Masui T, Kawaguchi M, Kawaguchi Y, et al. Expression of SOX9 in intraductal papillary mucinous neoplasms of the pancreas. Pancreas. 2014;43(1):7–14. doi: 10.1097/MPA.0b013e3182a70b2f.PubMedCrossRefGoogle Scholar
  26. 26.
    Shroff S, Rashid A, Wang H, Katz MH, Abbruzzese JL, Fleming JB, et al. SOX9: a useful marker for pancreatic ductal lineage of pancreatic neoplasms. Hum Pathol. 2014;45(3):456–63. doi: 10.1016/j.humpath.2013.10.008.PubMedCrossRefGoogle Scholar
  27. 27.
    Eser S, Schnieke A, Schneider G, Saur D. Oncogenic KRAS signalling in pancreatic cancer. Br J Cancer. 2014. doi:10.1038/bjc.2014.215.Google Scholar
  28. 28.
    Wei Y, Jiang Y, Zou F, Liu Y, Wang S, Xu N, et al. Activation of PI3K/Akt pathway by CD133-p85 interaction promotes tumorigenic capacity of glioma stem cells. Proc Natl Acad Sci USA. 2013;110(17):6829–34. doi: 10.1073/pnas.1217002110.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Liu PP, Liao J, Tang ZJ, Wu WJ, Yang J, Zeng ZL, et al. Metabolic regulation of cancer cell side population by glucose through activation of the Akt pathway. Cell Death Differ. 2014;21(1):124–35. doi: 10.1038/cdd.2013.131.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Yao J, Qian C. Inhibition of Notch3 enhances sensitivity to gemcitabine in pancreatic cancer through an inactivation of PI3K/Akt-dependent pathway. Med Oncol. 2010;27(3):1017–22. doi: 10.1007/s12032-009-9326-5.PubMedCrossRefGoogle Scholar
  31. 31.
    Maroulakou IG, Oemler W, Naber SP, Tsichlis PN. Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)-ErbB2/neu and MMTV-polyoma middle T transgenic mice. Cancer Res. 2007;67(1):167–77. doi: 10.1158/0008-5472.can-06-3782.PubMedCrossRefGoogle Scholar
  32. 32.
    Dillon RL, Marcotte R, Hennessy BT, Woodgett JR, Mills GB, Muller WJ. Akt1 and akt2 play distinct roles in the initiation and metastatic phases of mammary tumor progression. Cancer Res. 2009;69(12):5057–64. doi: 10.1158/0008-5472.can-08-4287.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Ikegami D, Akiyama H, Suzuki A, Nakamura T, Nakano T, Yoshikawa H, et al. Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways. Development. 2011;138(8):1507–19. doi: 10.1242/dev.057802.PubMedCrossRefGoogle Scholar
  34. 34.
    Cheng CC, Uchiyama Y, Hiyama A, Gajghate S, Shapiro IM, Risbud MV. PI3K/AKT regulates aggrecan gene expression by modulating Sox9 expression and activity in nucleus pulposus cells of the intervertebral disc. J Cell Physiol. 2009;221(3):668–76. doi: 10.1002/jcp.21904.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Suhua Xia
    • 1
  • Zhenyu Feng
    • 2
  • Xiaowei Qi
    • 3
  • Yuan Yin
    • 3
  • Jianqiang Jin
    • 3
  • Yufeng Wu
    • 4
  • Haorong Wu
    • 2
  • Yizhong Feng
    • 5
  • Min Tao
    • 1
    • 6
  1. 1.Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouPeople’s Republic of China
  2. 2.Department of General SurgeryThe Second Affiliated Hospital of Soochow UniversitySuzhouPeople’s Republic of China
  3. 3.Department of Pathology and Wuxi Oncology InstituteThe Affiliated Hospital of Jiangnan UniversityWuxiPeople’s Republic of China
  4. 4.Department of Internal Medicine, Henan Cancer HospitalThe Affiliated Cancer Hospital of Zhengzhou UniversityZhengzhouPeople’s Republic of China
  5. 5.Department of PathologyThe Second Affiliated Hospital of Soochow UniversitySuzhouPeople’s Republic of China
  6. 6.Jiangsu Institute of Clinical ImmunologySuzhouPeople’s Republic of China

Personalised recommendations