Advertisement

Pathology & Oncology Research

, Volume 25, Issue 1, pp 157–167 | Cite as

DDR2 and IFITM1 Are Prognostic Markers in Gallbladder Squamous Cell/Adenosquamous Carcinomas and Adenocarcinomas

  • Daiqiang Li
  • Zhulin YangEmail author
  • Ziru Liu
  • Qiong Zou
  • Yuan Yuan
Original Article

Abstract

This study was conducted to investigate the expressions of DDR2 and IFITM1 and their clinical and pathological significances in the rare type squamous cell/adenosquamous carcinomas (SC/ASC) and ordinary adenocarcinomas (AC) of gallbladder cancers. DDR2 and IFITM1 expression was examined in 69 SC/ASCs and 146 ACs using EnVision immunohistochemistry. Results showed that the percentage of positive DDR2 and IFITM1 expression was significantly higher in SC/ASC patients with high TNM stage, lymph node metastasis, invasion, and no resection surgery compared to patients with low TNM stages, no lymph node metastasis, no invasion, and resection surgery (P < 0.05 or P < 0.01). The positive rate of DDR2 was significantly higher in SC/ASC patients with large tumor sizes than patients with small tumor sizes (p < 0.05). The percentage of positive DDR2 and IFITM1 expressions was significantly higher in AC patients with high TNM stages that didn’t receive resection surgery compared to patients with low TNM stages that did receive resection surgery (P < 0.05 or P < 0.01). The positive rate of IFITM1 was significantly higher in AC patients with lymph node metastasis and invasion than in patients without metastasis and invasion (p < 0.05). Positive DDR2 and IFITM1 expression was closely associated with a decreased overall survival in SC/ASC and AC patients (P < 0.05 or P < 0.01). AUC analysis showed that DDR2 and IFITM1 was sensitive and specific for the diagnosis of SC/ASC (AUC = 0.740 and AUC =0.733, respectively) and AC (AUC = 0.710 and AUC =0.741, respectively). In conclusion, positive DDR2 and IFITM1 expression is a marker for the clinical severity, poor prognosis, and diagnosis of gallbladder SC/ASC and AC.

Keywords

Gallbladder Squamous cell carcinoma Adenosquamous carcinomas DDR2 IFITM 1 Immunohistochemistry 

References

  1. 1.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics, 2008. CA Cancer J Clin 58:71–96CrossRefGoogle Scholar
  2. 2.
    Jayaraman S, Jarnagin WR (2010) Management of gallbladder cancer. Gastroenterol Clin N Am 39:331–342CrossRefGoogle Scholar
  3. 3.
    Ootani T, Shirai Y, Tsukada K, Muto T (1992) Relationship between gallbladder carcinoma and the segmental type of adenomyomatosis of the gallbladder. Cancer 69:2647–2652CrossRefGoogle Scholar
  4. 4.
    Roa JC, Tapia O, Cakir A, Basturk O, Dursun N, Akdemir D, Saka B, Losada H, Bagci P, Adsay NV (2011) Squamous cell and adenosquamous carcinomas of the gallbladder: clinicopathological analysis of 34 cases identified in 606 carcinomas. Mod Pathol 24:1069–1078CrossRefGoogle Scholar
  5. 5.
    Reid KM, Ramos-Dela MA, Donohue JH (2007) Diagnosis and surgical management of gallbladder cancer: a review. J Gastrointest Surg 11:671–681CrossRefGoogle Scholar
  6. 6.
    Duffy A, Capanu M, Abou-Alfa GK, Huitzil D, Jarnagin W, Fong Y, D'Angelica M, Dematteo RP, Blumgart LH, O'Reilly EM (2008) Gallbladder cancer (GBC): 10-year experience at Memorial Sloan Kettering Cancer Centre (MSKCC). J Surg Oncol 98:485–489CrossRefGoogle Scholar
  7. 7.
    Hawkins WG, DeMatteo RP, Jarnagin WR, Ben-Porat L, Blumgart LH, Fong Y (2004) Jaundice predicts advanced disease and early mortality in patients with gallbladder cancer. Ann Surg Oncol 11:310–315CrossRefGoogle Scholar
  8. 8.
    Cubertafond P, Gainant A, Cucchiaro G (1994) Surgical treatment of 724 carcinomas of the gallbladder. Results of the French Surgical Association Survey. Ann Surg 219:275–280CrossRefGoogle Scholar
  9. 9.
    Lee SE, Jang JY, Kim SW, Han HS, Kim HJ, Yun SS, Cho BH, Yu HC, Lee WJ, Yoon DS et al (2014) Surgical strategy for T1 gallbladder cancer: a nationwide multicenter survey in South Korea. Ann Surg Oncol 21:3654–3660CrossRefGoogle Scholar
  10. 10.
    Fairweather M, Balachandran VP, D'Angelica MI (2016) Surgical management of biliary tract cancers. Chin Clin Oncol 5:63CrossRefGoogle Scholar
  11. 11.
    Chijiiwa K, Nakano K, Ueda J, Noshiro H, Nagai E, Yamaguchi K, Tanaka M (2001) Surgical treatment of patients with T2 gallbladder carcinoma invading the subserosal layer. J Am Coll Surg 192:600–607CrossRefGoogle Scholar
  12. 12.
    Horgan AM, Amir E, Walter T, Knox JJ (2012) Adjuvant therapy in the treatment of biliary cancer: a systematic review and meta-analysis. J Clin Oncol 30:1934–1940CrossRefGoogle Scholar
  13. 13.
    Sahu S, Sun W (2017) Targeted therapy in biliary tract cancers-current limitations and potentials in the future. J Gastrointest Oncol 8:324–336CrossRefGoogle Scholar
  14. 14.
    Michel G, Tonon T, Scornet D, Cock JM, Kloareg B (2010) The cell wall polysaccharide metabolism of the brown alga Ectocarpus siliculosus. Insights into the evolution of extracellular matrix polysaccharides in Eukaryotes. New Phytol 188:82–97CrossRefGoogle Scholar
  15. 15.
    Jabłońska-Trypuć A, Matejczyk M, Rosochacki S (2016) Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhib Med Chem 31(sup1):177–183CrossRefGoogle Scholar
  16. 16.
    Thakur V, Bedogni B (2016) The membrane tethered matrix metalloproteinase MT1-MMP at the forefront of melanoma cell invasion and metastasis. Pharmacol Res 111:17–22CrossRefGoogle Scholar
  17. 17.
    Vogel W, Gish GD, Alves F, Pawson T (1997) The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell 1:13–23CrossRefGoogle Scholar
  18. 18.
    Sivakumar L, Agarwal G (2010) The influence of discoidin domain receptor 2 on the persistence length of collagen type I fibers. Biomaterials 31:4802–4808CrossRefGoogle Scholar
  19. 19.
    Herrera-Herrera ML, Quezada-Calvillo R (2012) DDR2 plays a role in fibroblast migration independent of adhesion ligand and collagen activated DDR2 tyrosine kinase. Biochem Biophys Res Commun 429:39–44CrossRefGoogle Scholar
  20. 20.
    Badiola I, Villacé P, Basaldua I, Olaso E (2011) Down regulation of discoidin domain receptor 2 in A375 human melanoma cells reduces its experimental liver metastasis ability. Oncol Rep 26:971–978Google Scholar
  21. 21.
    Badiola I, Olaso E, Crende O, Friedman SL, Vidal-Vanaclocha F (2012) Discoidin domain receptor 2 deficiency predisposes hepatic tissue to colon carcinoma metastasis. Gut 61:1465–1472CrossRefGoogle Scholar
  22. 22.
    Ren T, Zhang J, Zhang J, Liu X, Yao L (2013) Increased expression of discoidin domain receptor 2 (DDR2): a novel independent prognostic marker of worse outcome in breast cancer patients. Med Oncol 30:397CrossRefGoogle Scholar
  23. 23.
    Sasaki H, Shitara M, Yokota K, Okuda K, Hikosaka Y, Moriyama S, Yano M, Fujii Y (2012) DDR2 polymorphisms and mRNA expression in lung cancers of Japanese patients. Oncol Lett 4:33–37CrossRefGoogle Scholar
  24. 24.
    Park JW, Lee YS, Kim JS, Lee SK, Kim BH, Lee JA, Lee NO, Kim SH, Hong EK (2015) Downregulation of discoidin domain receptor 2 decreases tumor growth of hepatocellularcarcinoma. J Cancer Res Clin Oncol 141:197319–197383Google Scholar
  25. 25.
    Wang YG, Xu L, Jia RR, Wu Q, Wang T, Wei J, Ma JL, Shi M, Li ZS (2016) DDR2 induces gastric cancer cell activities via activating mTORC2 signaling and is associated with clinicopathological characteristics of gastric cancer. Dig Dis Sci 61:2272–2283CrossRefGoogle Scholar
  26. 26.
    Azemikhah M, Ashtiani HA, Aghaei M, Rastegar H (2015) Evaluation of discoidin domain receptor-2 (DDR2) expression level in normal, benign, and malignant human prostate tissues. Res Pharm Sci 10:356–363Google Scholar
  27. 27.
    Kim D, Ko P, You E, Rhee S (2014) The intracellular juxtamembrane domain of discoidin domain receptor 2 (DDR2) is essential for receptor activation and DDR2-mediated cancer progression. Int J Cancer 135:2547–2557CrossRefGoogle Scholar
  28. 28.
    Fan Y, Xu Z, Fan J, Huang L, Ye M, Shi K, Huang Z, Liu Y, He L, Huang J, Wang Y, Li Q (2016) Prognostic significance of discoidin domain receptor 2 (DDR2) expression in ovarian cancer. Am J Transl Res 8:2845–2850Google Scholar
  29. 29.
    Johnson MC, Sangrador-Vegas A, Smith TJ, Cairns MT (2006) Cloning and characterization of two genes encoding rainbow trout homologues of the IFITM protein family. Vet Immunol Immunopathol 110:357–362CrossRefGoogle Scholar
  30. 30.
    Ogony J, Choi HJ, Lui A, Cristofanilli M, Lewis-Wambi J (2016) Interferon-induced transmembrane protein 1 (IFITM1) overexpression enhances the aggressive phenotype of SUM149 inflammatory breast cancer cells in a signal transducer and activator of transcription 2 (STAT2)-dependent manner. Breast Cancer Res 18:25CrossRefGoogle Scholar
  31. 31.
    Lee J, Goh SH, Song N, Hwang JA, Nam S, Choi IJ, Shin A, Kim IH, Ju MH, Jeong JS, Lee YS (2012) Overexpression of IFITM1 has clinicopathologic effects on gastric cancer and is regulated by an epigenetic mechanism. Am J Pathol 181:43–52CrossRefGoogle Scholar
  32. 32.
    He J, Li J, Feng W, Chen L, Yang K (2015) Prognostic significance of INF-induced transmembrane protein 1 in colorectal cancer. Int J Clin Exp Pathol 8:16007–16013Google Scholar
  33. 33.
    Kim NH, Sung HY, Choi EN, Lyu D, Choi HJ, Ju W, Ahn JH (2014) Aberrant DNA methylation in the IFITM1 promoter enhances the metastatic phenotype in an intraperitoneal xenograft model of human ovarian cancer. Oncol Rep 31:2139–2146CrossRefGoogle Scholar
  34. 34.
    Yu F, Ng SS, Chow BK, Sze J, Lu G, Poon WS, Kung HF, Lin MC (2011) Knockdown of interferon-induced transmembrane protein 1 (IFITM1) inhibits proliferation, migration, and invasion of glioma cells. J Neuro-Oncol 103:187–195CrossRefGoogle Scholar
  35. 35.
    Kim JY, Kim H, Suk K, Lee WH (2010) Activation of CD147 with cyclophilin a induces the expression of IFITM1 through ERK and PI3K in THP-1 cells. Mediat Inflamm 2010:821940Google Scholar
  36. 36.
    Deraz EM, Kudo Y, Yoshida M, Obayashi M, Tsunematsu T, Tani H, Siriwardena SB, Keikhaee MR, Qi G, Iizuka S et al (2011) MMP-10/stromelysin-2 promotes invasion of head and neck cancer. PLoS One 6:e25438CrossRefGoogle Scholar
  37. 37.
    He JD, Luo HL, Li J, Feng WT, Chen LB (2012) Influences of the interferon induced transmembrane protein 1 on the proliferation, invasion, and metastasis of the colorectal cancer SW480 cell lines. Chin Med J 125:517–522Google Scholar
  38. 38.
    Kondo M, Dono K, Sakon M, Shimizu J, Nagano H, Nakamori S, Umeshita K, Wakasa K, Monden M (2002) Adenosquamous carcinoma of the gallbladder. Hepato-Gastroenterology 49:1230–1234Google Scholar
  39. 39.
    Muzio G, Maggiora M, Paiuzzi E, Oraldi M, Canuto RA (2012) Aldehyde dehydrogenases and cell proliferation. Free Radic Biol Med 52:735–746CrossRefGoogle Scholar
  40. 40.
    Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141:1117–1134CrossRefGoogle Scholar
  41. 41.
    Evans SS, Lee DB, Han T, Tomasi TB, Evans RL (1990) Monoclonal antibody to the interferon-inducible protein leu-13 triggers aggregation and inhibits proliferation of leukemic B cells. Blood 76:2583–2593Google Scholar
  42. 42.
    Hatano H, Kudo Y, Ogawa I, Tsunematsu T, Kikuchi A, Abiko Y, Takata T (2008) IFN-induced transmembrane protein 1 promotes invasion at early stage of head and neck cancer progression. Clin Cancer Res 14:6097–6105CrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2017

Authors and Affiliations

  • Daiqiang Li
    • 1
  • Zhulin Yang
    • 2
    Email author
  • Ziru Liu
    • 2
  • Qiong Zou
    • 3
  • Yuan Yuan
    • 3
  1. 1.Department of Pathology, Second Xiangya HospitalCentral South UniversityChangshaChina
  2. 2.Department of General Surgery, Second Xiangya HospitalCentral South UniversityChangshaChina
  3. 3.Department of Pathology, Third Xiangya HospitalCentral South UniversityChangshaChina

Personalised recommendations