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01-02-2012 | Head and Neck Oncology

Overexpression of SIP1 and Downregulation of E-cadherin Predict Delayed Neck Metastasis in Stage I/II Oral Tongue Squamous Cell Carcinoma After Partial Glossectomy

Authors: Koji Sakamoto, MD, Yorihisa Imanishi, MD, Toshiki Tomita, MD, Masayuki Shimoda, MD, Kaori Kameyama, MD, Katsushi Shibata, MD, Nobuya Sakai, PhD, Hiroyuki Ozawa, MD, Seiji Shigetomi, MD, Ryoichi Fujii, MD, Masato Fujii, MD, Kaoru Ogawa, MD

Published in: Annals of Surgical Oncology | Issue 2/2012

Abstract

Background

Patients with clinical stage I/II (T1–2N0M0) oral tongue squamous cell carcinoma (TSCC) usually undergo partial glossectomy alone. However, 14–48% of them develop delayed neck metastasis (DNM), which may lead to an unfavorable course. Recently epithelial-to-mesenchymal transition (EMT) has been thought to play a crucial role in cancer metastasis. The present study aimed to examine the associations of EMT-involved molecular factors and clinicopathological factors with DNM in stage I/II TSCC.

Methods

mRNA expression levels of E-cadherin and its transcriptional repressors (snail, SIP1, and twist) in 7 head and neck squamous cell carcinoma (HNSCC) cell lines were evaluated by quantitative real-time PCR. Clinicopathological parameters and immunohistochemical expressions of E-cadherin and its repressors were examined in surgical specimens of 37 stage I/II TSCC patients who underwent partial glossectomy alone.

Results

In HNSCC cells, E-cadherin expression was inversely correlated with SIP1 expression (P = 0.023). Univariate analysis of immunohistochemistry showed that overexpression of SIP1 and loss of E-cadherin were significantly correlated with DNM, although no inverse correlation was found between E-cadherin and its repressors. Multiple logistic regression analysis including clinicopathological and molecular factors revealed that overexpression of SIP1 (P = 0.005), loss of E-cadherin (P = 0.046), and vascular invasion (P = 0.024) were independently correlated with DNM.

Conclusions

These results suggest that development of DNM in stage I/II TSCC is closely related to induction of EMT in primary tumor cells. Especially, SIP1 and E-cadherin are considered to be the possible markers for selecting patients at high risk of DNM.

DiTroia JF. Nodal metastases and prognosis in carcinoma of the oral cavity. Otolaryngol Clin North Am. 1972;5:333–42.PubMed

Cerezo L, Millan I, Torre A, Aragon G, Otero J. Prognostic factors for survival and tumor control in cervical lymph node metastases from head and neck cancer. A multivariate study of 492 cases. Cancer. 1992;69:1224–34.PubMedCrossRef

Leemans CR, Tiwari R, Nauta JJ, van der Waal I, Snow GB. Recurrence at the primary site in head and neck cancer and the significance of neck lymph node metastases as a prognostic factor. Cancer. 1994;73:187–90.PubMedCrossRef

Pentenero M, Gandolfo S, Carrozzo M. Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: a review of the literature. Head Neck. 2005;27:1080–91.PubMedCrossRef

Asakage T, Yokose T, Mukai K, Tsugane S, Tsubono Y, Asai M, et al. Tumor thickness predicts cervical metastasis in patients with stage I/II carcinoma of the tongue. Cancer. 1998;82:1443–8.PubMedCrossRef

Kurokawa H, Yamashita Y, Takeda S, Zhang M, Fukuyama H, Takahashi T. Risk factors for late cervical lymph node metastases in patients with stage I or II carcinoma of the tongue. Head Neck. 2002;24:731–6.PubMedCrossRef

Ho CM, Lam KH, Wei WI, Lau SK, Lam LK. Occult lymph node metastasis in small oral tongue cancers. Head Neck. 1992;14:359–63.PubMedCrossRef

Cunningham MJ, Johnson JT, Myers EN, Schramm VL, Jr., Thearle PB. Cervical lymph node metastasis after local excision of early squamous cell carcinoma of the oral cavity. Am J Surg. 1986;152:361–6.PubMedCrossRef

Goto M, Hasegawa Y, Terada A, Hyodo I, Hanai N, Ijichi K, et al. Prognostic significance of late cervical metastasis and distant failure in patients with stage I and II oral tongue cancers. Oral Oncol. 2005;41:62–9.PubMedCrossRef

10.

Weiss MH, Harrison LB, Isaacs RS. Use of decision analysis in planning a management strategy for the stage N0 neck. Arch Otolaryngol Head Neck Surg. 1994;120:699–702.PubMedCrossRef

11.

Myo K, Uzawa N, Miyamoto R, Sonoda I, Yuki Y, Amagasa T. Cyclin D1 gene numerical aberration is a predictive marker for occult cervical lymph node metastasis in TNM Stage I and II squamous cell carcinoma of the oral cavity. Cancer. 2005;104:2709–16.PubMedCrossRef

12.

Suzuki F, Oridate N, Homma A, Nakamaru Y, Nagahashi T, Yagi K, et al. S100A2 expression as a predictive marker for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral cavity. Oncol Rep. 2005;14:1493–8.PubMed

13.

Lim SC, Zhang S, Ishii G, Endoh Y, Kodama K, Miyamoto S, et al. Predictive markers for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral tongue. Clin Cancer Res. 2004;10:166–72.PubMedCrossRef

14.

Hoon DS, Kitago M, Kim J, Mori T, Piris A, Szyfelbein K, et al. Molecular mechanisms of metastasis. Cancer Metastasis Rev. 2006;25:203–20.PubMedCrossRef

15.

Zavadil J, Haley J, Kalluri R, Muthuswamy SK, Thompson E. Epithelial-mesenchymal transition. Cancer Res. 2008;68:9574–7.PubMedCrossRef

16.

Berx G, Raspe E, Christofori G, Thiery JP, Sleeman JP. Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer. Clin Exp Metastasis. 2007;24:587–97.PubMedCrossRef

17.

Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.PubMedCrossRef

18.

Hirohashi S. Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am J Pathol. 1998;153:333–9.PubMedCrossRef

19.

Baranwal S, Alahari SK. Molecular mechanisms controlling E-cadherin expression in breast cancer. Biochem Biophys Res Commun. 2009;384:6–11.PubMedCrossRef

20.

Beavon IR. The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation. Eur J Cancer. 2000;36:1607–20.PubMedCrossRef

21.

Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7:415–28.PubMedCrossRef

22.

Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell. 2001;7:1267–78.PubMedCrossRef

23.

Mandal M, Myers JN, Lippman SM, Johnson FM, Williams MD, Rayala S, et al. Epithelial to mesenchymal transition in head and neck squamous carcinoma: association of Src activation with E-cadherin down-regulation, vimentin expression, and aggressive tumor features. Cancer. 2008;112:2088–100.PubMedCrossRef

24.

Muller S, Su L, Tighiouart M, Saba N, Zhang H, Shin DM, et al. Distinctive E-cadherin and epidermal growth factor receptor expression in metastatic and nonmetastatic head and neck squamous cell carcinoma: predictive and prognostic correlation. Cancer. 2008;113:97–107.PubMedCrossRef

25.

Bosch FX, Andl C, Abel U, Kartenbeck J. E-cadherin is a selective and strongly dominant prognostic factor in squamous cell carcinoma: a comparison of E-cadherin with desmosomal components. Int J Cancer. 2005;114:779–90.PubMedCrossRef

26.

Takes RP, Baatenburg De Jong RJ, Alles MJ, et al. Markers for nodal metastasis in head and neck squamous cell cancer. Arch Otolaryngol Head Neck Surg. 2002;128:512–8.PubMed

27.

Nakanishi Y, Ochiai A, Kato H, Tachimori Y, Igaki H, Hirohashi S. Clinicopathological significance of tumor nest configuration in patients with esophageal squamous cell carcinoma. Cancer. 2001;91:1114–20.PubMedCrossRef

28.

Ng SH, Yen TC, Liao CT, Chang JT, Chan SC, Ko SF, et al. 18F-FDG PET and CT/MRI in oral cavity squamous cell carcinoma: a prospective study of 124 patients with histologic correlation. J Nucl Med. 2005;46:1136–43.PubMed

29.

Woolgar JA. Pathology of the N0 neck. Br J Oral Maxillofac Surg. 1999;37:205–9.PubMedCrossRef

30.

Chung CH, Parker JS, Karaca G, Wu J, Funkhouser WK, Moore D, et al. Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell. 2004;5:489–500.PubMedCrossRef

31.

Roepman P, Wessels LF, Kettelarij N, Kemmeren P, Miles AJ, Lijnzaad P, et al. An expression profile for diagnosis of lymph node metastases from primary head and neck squamous cell carcinomas. Nat Genet. 2005;37:182–6.PubMedCrossRef

32.

Civantos FJ, Zitsch RP, Schuller DE, Agrawal A, Smith RB, Nason R, Petruzelli G, et al. Sentinel lymph node biopsy accurately stages the regional lymph nodes for T1–T2 oral squamous cell carcinomas: results of a prospective multi-institutional trial. J Clin Oncol. 2010;28:1395–400.PubMedCrossRef

33.

Goerkem M, Braun J, Stoeckli SJ. Evaluation of clinical and histomorphological parameters as potential predictors of occult metastases in sentinel lymph nodes of early squamous cell carcinoma of the oral cavity. Ann Surg Oncol. 2010;17:527–35.PubMedCrossRef

34.

Stoeckli SJ. Sentinel node biopsy for oral and oropharyngeal squamous cell carcinoma of the head and neck. Laryngoscope. 2007;117:1539–51.PubMedCrossRef

35.

Woolgar JA, Scott J. Prediction of cervical lymph node metastasis in squamous cell carcinoma of the tongue/floor of mouth. Head Neck. 1995;17:463–72.PubMedCrossRef

36.

Maeda G, Chiba T, Okazaki M, Satoh T, Taya Y, Aoba T, et al. Expression of SIP1 in oral squamous cell carcinomas: implications for E-cadherin expression and tumor progression. Int J Oncol. 2005;27:1535–41.PubMed

37.

Yokoyama K, Kamata N, Hayashi E, Hoteiya T, Ueda N, Fujimoto R, et al. Reverse correlation of E-cadherin and snail expression in oral squamous cell carcinoma cells in vitro. Oral Oncol. 2001;37:65–71.PubMedCrossRef

38.

Miyoshi A, Kitajima Y, Sumi K, Sato K, Hagiwara A, Koga Y, et al. Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells. Br J Cancer. 2004;90:1265–73.PubMedCrossRef

39.

Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R, et al. Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am J Pathol. 2002;161:1881–91.PubMedCrossRef

40.

Rashid MG, Sanda MG, Vallorosi CJ, Rios-Doria J, Rubin MA, Day ML. Posttranslational truncation and inactivation of human E-cadherin distinguishes prostate cancer from matched normal prostate. Cancer Res. 2001;61:489–92.PubMed

41.

Lochter A, Galosy S, Muschler J, Freedman N, Werb Z, Bissell MJ. Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J Cell Biol. 1997;139:1861–72.PubMedCrossRef

42.

Bindels S, Mestdagt M, Vandewalle C, Jacobs N, Volders L, Noël A, et al. Regulation of vimentin by SIP1 in human epithelial breast tumor cells. Oncogene. 2006;25:4975–85.PubMedCrossRef

43.

Imanishi Y, Fujii M, Tokumaru Y, Tomita T, Kanke M, Kanzaki J, et al. Clinical significance of expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 in human head and neck squamous cell carcinoma. Hum Pathol. 2000;31:895–904.PubMedCrossRef

44.

Rosenthal EL, Matrisian LM. Matrix metalloproteases in head and neck cancer. Head Neck. 2006;28:639–48.PubMedCrossRef

45.

Vandewalle C, Comijn J, De Craene B, Vermassen P, Bruyneel E, Andersen H, et al. SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell–cell junctions. Nucleic Acids Res. 2005;33:6566–78.PubMedCrossRef

Title: Overexpression of SIP1 and Downregulation of E-cadherin Predict Delayed Neck Metastasis in Stage I/II Oral Tongue Squamous Cell Carcinoma After Partial Glossectomy
Authors: Koji Sakamoto, MD
Yorihisa Imanishi, MD
Toshiki Tomita, MD
Masayuki Shimoda, MD
Kaori Kameyama, MD
Katsushi Shibata, MD
Nobuya Sakai, PhD
Hiroyuki Ozawa, MD
Seiji Shigetomi, MD
Ryoichi Fujii, MD
Masato Fujii, MD
Kaoru Ogawa, MD
Publication date: 01-02-2012
Publisher: Springer-Verlag
Published in: Annals of Surgical Oncology / Issue 2/2012
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-011-2052-1

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Overexpression of SIP1 and Downregulation of E-cadherin Predict Delayed Neck Metastasis in Stage I/II Oral Tongue Squamous Cell Carcinoma After Partial Glossectomy

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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