J Pathol Transl Med.  2019 Jan;53(1):13-22. 10.4132/jptm.2018.11.12.

Prognostic Role of S100A8 and S100A9 Protein Expressions in Non-small Cell Carcinoma of the Lung

• Koh HM
• An HJ
• Ko GH
• Lee JH
• Lee JS
• Kim DC
• Yang JW
• Kim MH
• Kim SH
• Jeon KN
• Lee GW
• Jang SM
• Song DH

• KMID: 2437574
• DOI: http://doi.org/10.4132/jptm.2018.11.12

Abstract

BACKGROUND
S100A8 and S100A9 have been gaining recognition for modulating tumor growthand metastasis. This study aimed at evaluating the clinical significance of S100A8 and S100A9 innon-small cell lung cancer (NSCLC).
METHODS
We analyzed the relationship between S100A8and S100A9 expressions, clinicopathological characteristics, and prognostic significance in tumorcells and peritumoral inflammatory cells.
RESULTS
The positive staining of S100A8 in tumorcells was significantly increased in male (p < .001), smoker (p = .034), surgical method other thanlobectomy (p = .024), squamous cell carcinoma (SQCC) (p < .001) and higher TNM stage (p = .022)compared with female, non-smoker, lobectomy, adenocarcinoma (ADC), and lower stage. Theproportion of tumor cells stained for S100A8 was related to histologic type (p < .001) and patientsex (p = .027). The proportion of inflammatory cells stained for S100A8 was correlated with patientage (p = .022), whereas the proportion of inflammatory cells stained for S100A9 was correlatedwith patient sex (p < .001) and smoking history (p = .031). Moreover, positive staining in tumorcells, more than 50% of the tumor cells stained and less than 30% of the inflammatory cellsstained for S100A8 and S100A9 suggested a tendency towards increased survivability in SQCCbut towards decreased survivability in ADC.
CONCLUSIONS
S100A8 and S100A9 expressions might be potential prognostic markers in patients with NSCLC.

Keyword

S100A8; S100A9; Carcinoma, non-small cell lung; Prognosis

MeSH Terms

Adenocarcinoma
Calgranulin B*
Carcinoma, Non-Small-Cell Lung
Carcinoma, Squamous Cell
Female
Humans
Lung Neoplasms
Lung*
Male
Methods
Neoplasm Metastasis
Prognosis
Smoke
Smoking
Calgranulin B
Smoke

Figure

• 

  Fig. 1. S100A8 and S100A9 expressions in non-small cell lung cancer. Tumor cells and inflammatory cells stained for S100A8 in squamous cell carcinoma (A), inflammatory cells stained for S100A8 in adenocarcinoma (B), tumor cells and inflammatory cells stained for S100A9 in squamous cell carcinoma (C), tumor cells and inflammatory cells stained for S100A9 in adenocarcinoma (D).

• 

  Fig. 2. Kaplan-Meier survival analysis of survival curves based on S100A8 and S100A9 expressions in patients with squamous cell carcinoma. The groups with positive staining in tumor cells (A, D), the groups with more than 50% of the tumor cells (B, E) stained and the groups with less than 30% of the inflammatory cells (C, F) stained for S100A8 and S100A9 reveal a tendency towards increased survivability compared with the groups showing negative staining, less than 50% of the tumor cells stained and more than 30% of the inflammatory cells stained.

• 

  Fig. 3. Kaplan-Meier survival analysis of survival curves based on S100A8 and S100A9 expressions in patients with adenocarcinoma. The groups with positive staining in tumor cells (A, D), the groups with more than 50% of the tumor cells (B, E) stained and the groups with less than 30% of the inflammatory cells (C, F) stained for S100A8 and S100A9 reveal a trend towards decreased survivability compared with the groups showing negative staining, less than 50% of the tumor cells stained and more than 30% of the inflammatory cells stained.

Reference

1. Jo YM, Park TI, Lee HY, Jeong JY, Lee WK. Prognostic significance of aquaporin 5 expression in non-small cell lung cancer. J Pathol Transl Med. 2016; 50:122–8.

2. Lee SH, Kim WS, Choi YD, et al. Analysis of mutations in epidermal growth factor receptor gene in Korean patients with non-small cell lung cancer: summary of a nationwide survey. J Pathol Transl Med. 2015; 49:481–8.

3. Fan B, Zhang LH, Jia YN, et al. Presence of S100A9-positive inflammatory cells in cancer tissues correlates with an early stage cancer and a better prognosis in patients with gastric cancer. BMC Cancer. 2012; 12:316.

4. Yasar O, Akcay T, Obek C, Turegun FA. Significance of S100A8, S100A9 and calprotectin levels in bladder cancer. Scand J Clin Lab Invest. 2017; 77:437–41.

5. Salama I, Malone PS, Mihaimeed F, Jones JL. A review of the S100 proteins in cancer. Eur J Surg Oncol. 2008; 34:357–64.

6. Gebhardt C, Nemeth J, Angel P, Hess J. S100A8 and S100A9 in inflammation and cancer. Biochem Pharmacol. 2006; 72:1622–31.

7. Lang B, Shang C, Meng L. Targeted silencing of S100A8 gene by miR-24 to increase chemotherapy sensitivity of endometrial carcinoma cells to paclitaxel. Med Sci Monit. 2016; 22:1953–8.

8. Srikrishna G. S100A8 and S100A9: new insights into their roles in malignancy. J Innate Immun. 2012; 4:31–40.

9. Hiratsuka S, Watanabe A, Aburatani H, Maru Y. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol. 2006; 8:1369–75.

10. Lim SY, Yuzhalin AE, Gordon-Weeks AN, Muschel RJ. Tumor-infiltrating monocytes/macrophages promote tumor invasion and migration by upregulating S100A8 and S100A9 expression in cancer cells. Oncogene. 2016; 35:5735–45.

11. Hiratsuka S, Watanabe A, Sakurai Y, et al. The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nat Cell Biol. 2008; 10:1349–55.

12. Weidle UH, Birzele F, Kollmorgen G, Rüger R. The multiple roles of exosomes in metastasis. Cancer Genomics Proteomics. 2017; 14:1–15.

13. Armstrong D, Wildman DE. Extracellular vesicles and the promise of continuous liquid biopsies. J Pathol Transl Med. 2018; 52:1–8.

14. Song DH, Ko GH, Lee JH, et al. Myoferlin expression in non-small cell lung cancer: prognostic role and correlation with VEGFR-2 expression. Oncol Lett. 2016; 11:998–1006.

15. Song DH, Ko GH, Lee JH, et al. Prognostic role of myoferlin expression in patients with clear cell renal cell carcinoma. Oncotarget. 2017; 8:89033–9.

16. Choi DK, Li ZJ, Chang IK, et al. Clinicopathological roles of S100A8 and S100A9 in cutaneous squamous cell carcinoma in vivo and in vitro. Arch Dermatol Res. 2014; 306:489–96.

17. Arai K, Takano S, Teratani T, Ito Y, Yamada T, Nozawa R. S100A8 and S100A9 overexpression is associated with poor pathological parameters in invasive ductal carcinoma of the breast. Curr Cancer Drug Targets. 2008; 8:243–52.

18. Su YJ, Xu F, Yu JP, Yue DS, Ren XB, Wang CL. Up-regulation of the expression of S100A8 and S100A9 in lung adenocarcinoma and its correlation with inflammation and other clinical features. Chin Med J (Engl). 2010; 123:2215–20.

19. Arai K, Teratani T, Nozawa R, Yamada T. Immunohistochemical investigation of S100A9 expression in pulmonary adenocarcinoma: S100A9 expression is associated with tumor differentiation. Oncol Rep. 2001; 8:591–6.

20. Huang H, Huang Q, Tang T, et al. Clinical significance of calciumbinding protein S100A8 and S100A9 expression in non-small cell lung cancer. Thorac Cancer. 2018; 9:800–4.

21. Zhang X, Ai F, Li X, et al. Inflammation-induced S100A8 activates Id3 and promotes colorectal tumorigenesis. Int J Cancer. 2015; 137:2803–14.

22. Zhu H, Wu TC, Chen WQ, et al. Roles of galectin-7 and S100A9 in cervical squamous carcinoma: clinicopathological and in vitro evidence. Int J Cancer. 2013; 132:1051–9.

23. Roesch Ely M, Nees M, Karsai S, et al. Transcript and proteome analysis reveals reduced expression of calgranulins in head and neck squamous cell carcinoma. Eur J Cell Biol. 2005; 84:431–44.

24. Kong JP, Ding F, Zhou CN, et al. Loss of myeloid-related proteins 8 and myeloid-related proteins 14 expression in human esophageal squamous cell carcinoma correlates with poor differentiation. World J Gastroenterol. 2004; 10:1093–7.

25. Funk S, Mark R, Bayo P, et al. High S100A8 and S100A12 protein expression is a favorable prognostic factor for survival of oropharyngeal squamous cell carcinoma. Int J Cancer. 2015; 136:2037–46.

26. Voss A, Bode G, Sopalla C, et al. Expression of S100A8/A9 in HaCaT keratinocytes alters the rate of cell proliferation and differentiation. FEBS Lett. 2011; 585:440–6.

27. El-Rifai W, Moskaluk CA, Abdrabbo MK, et al. Gastric cancers overexpress S100A calcium-binding proteins. Cancer Res. 2002; 62:6823–6.

28. Seth A, Kitching R, Landberg G, Xu J, Zubovits J, Burger AM. Gene expression profiling of ductal carcinomas in situ and invasive breast tumors. Anticancer Res. 2003; 23:2043–51.

29. Stulík J, Osterreicher J, Koupilová K, et al. The analysis of S100A9 and S100A8 expression in matched sets of macroscopically normal colon mucosa and colorectal carcinoma: the S100A9 and S100A8 positive cells underlie and invade tumor mass. Electrophoresis. 1999; 20:1047–54.

30. Shen J, Person MD, Zhu J, Abbruzzese JL, Li D. Protein expression profiles in pancreatic adenocarcinoma compared with normal pancreatic tissue and tissue affected by pancreatitis as detected by twodimensional gel electrophoresis and mass spectrometry. Cancer Res. 2004; 64:9018–26.

31. Hermani A, Hess J, De Servi B, et al. Calcium-binding proteins S100A8 and S100A9 as novel diagnostic markers in human prostate cancer. Clin Cancer Res. 2005; 11:5146–52.

32. Arai K, Teratani T, Kuruto-Niwa R, Yamada T, Nozawa R. S100A9 expression in invasive ductal carcinoma of the breast: S100A9 expression in adenocarcinoma is closely associated with poor tumour differentiation. Eur J Cancer. 2004; 40:1179–87.

33. Ito Y, Arai K, et al. S100A9 expression is significantly linked to dedifferentiation of thyroid carcinoma. Pathol Res Pract. 2005; 201:551–6.

34. DeNardo DG, Andreu P, Coussens LM. Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Rev. 2010; 29:309–16.

35. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012; 12:253–68.