CCID_A_285564 209..216

Department of Pathology Anatomy, Faculty of Medicine, Universitas Padjadjaran/Dr. Hasan Sadikin General Hospital, Bandung, Indonesia Introduction: Acral melanoma (AM) has a poor prognosis since it is easily metastatic and resistant to chemo and immunotherapy. Cyclooxygenase-2 (COX-2) is an enzyme that plays a role in the carcinogenesis process. The increased expression of COX-2 has an impact on increasing levels of Myeloid-Derived Suppressor Cell (MDSC), which is a key regulator of immune. The increase in MDSC produces Transforming Growth Factor β1 (TGF-β1), which will suppress Natural Killer (NK) cells and Dendritic Cells (DC) function so that tumor cells are spared from the immune systems and are easier to invade surrounding tissues. Purpose: This study aimed to determine the role of COX-2 and TGF-β1 on the depth of invasion on AM. Materials and Methods: This study was a cross-sectional observational study on 40 paraffin blocks of AM cases during 2014–2019 in the Department of Pathology Anatomy, Faculty of Medicine, Dr. Hasan Sadikin General Hospital, Bandung. The depth of invasion of all samples was measured by dotSlide imaging software and the immunohistochemical staining of COX-2 and TGF-β1 was performed. The association between COX-2 and TGF-β1 expression and AM depth of invasion were analyzed using Mann Whitney. Results: The result showed a significant association between COX-2 and TGF-β1 expression and depth of invasion on AM. COX-2 expression had a significant association with TGF-β1 expression (0.0001). Through multivariate analysis, it was found that COX-2 had the greatest association with the depth of invasion (p=0.0001). Conclusion: The findings showed that increasing expression of COX-2 in AM is associated with the depth of invasion by increasing TGF-β1 and it might play important roles during the invasion process of AM.

[1]  A. Tackett,et al.  Current state of melanoma diagnosis and treatment , 2019, Cancer biology & therapy.

[2]  M. Ghasemi,et al.  The role of immunohistochemistry expression of COX-2 in differentiating pigmented benign and malignant skin neoplasms , 2019, Medical journal of the Islamic Republic of Iran.

[3]  H. Ayatollahi,et al.  Evaluation of Cyclooxygenase-2 Expression in Association with Clinical-Pathological Factors in Malignant Melanoma , 2019, Iranian journal of pathology.

[4]  M. Najafi,et al.  Cyclooxygenase‐2 in cancer: A review , 2018, Journal of cellular physiology.

[5]  S. Patel,et al.  Systemic Therapy for Mucosal, Acral and Uveal Melanoma , 2019, Cutaneous Melanoma.

[6]  R. Brekken,et al.  Cyclooxygenase-2 Inhibition Potentiates the Efficacy of Vascular Endothelial Growth Factor Blockade and Promotes an Immune Stimulatory Microenvironment in Preclinical Models of Pancreatic Cancer , 2018, Molecular Cancer Research.

[7]  D. Edwards,et al.  TGF-β1 programmed myeloid-derived suppressor cells (MDSC) acquire immune-stimulating and tumor killing activity capable of rejecting established tumors in combination with radiotherapy , 2018, Oncoimmunology.

[8]  F. Tas,et al.  Acral Lentiginous Melanoma Is Associated with Certain Poor Prognostic Histopathological Factors but May Not be Correlated with Nodal Involvement, Recurrence, and a Worse Survival , 2018, Pathobiology.

[9]  H. Usman,et al.  The Major Role of NF-κB in the Depth of Invasion on Acral Melanoma by Decreasing CD8+ T Cells , 2018, Journal of pathology and translational medicine.

[10]  L. Looi,et al.  Cyclooxygenase-2 (COX2) expression in adenocarcinoma surpasses that of squamous cell carcinoma in the uterine cervix. , 2017, The Malaysian journal of pathology.

[11]  B. Becher,et al.  The Cytokine TGF‐&bgr; Promotes the Development and Homeostasis of Alveolar Macrophages , 2017, Immunity.

[12]  Kotryna Seip.  Tumor – microenvironment interactions in malignant melanoma. Impact on metastatic phenotype and drug resistance , 2017 .

[13]  Shuangge Ma,et al.  Racial differences in six major subtypes of melanoma: descriptive epidemiology , 2016, BMC Cancer.

[14]  B. Dai,et al.  Acral Melanoma in Chinese: A Clinicopathological and Prognostic Study of 142 cases , 2016, Scientific Reports.

[15]  Bing Liu,et al.  Cyclooxygenase-2 promotes tumor growth and suppresses tumor immunity , 2015, Cancer Cell International.

[16]  Gang Chen,et al.  Epithelial-Mesenchymal Transition in Keratocystic Odontogenic Tumor: Possible Role in Locally Aggressive Behavior , 2015, BioMed research international.

[17]  B. Seliger,et al.  Inhibition of Tumor-Derived Prostaglandin-E2 Blocks the Induction of Myeloid-Derived Suppressor Cells and Recovers Natural Killer Cell Activity , 2014, Clinical Cancer Research.

[18]  Deepak Mittal,et al.  New insights into cancer immunoediting and its three component phases--elimination, equilibrium and escape. , 2014, Current opinion in immunology.

[19]  G. Sa,et al.  Role of Cyclooxygenase 2 (COX-2) in Prognosis of Breast Cancer , 2014, Indian Journal of Surgical Oncology.

[20]  Hui-Li Qu,et al.  Transforming growth factor-β 1 enhances the invasiveness of breast cancer cells by inducing a Smad2-dependent epithelial-to-mesenchymal transition. , 2013, Oncology reports.

[21]  P. Kalinski,et al.  Key role of the positive feedback between PGE2 and COX2 in the biology of myeloid-derived suppressor cells , 2012, Oncoimmunology.

[22]  W. Schiemann,et al.  PGE2 receptor EP2 mediates the antagonistic effect of COX‐2 on TGF‐β signaling during mammary tumorigenesis , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[23]  D. Alberts,et al.  Analysis of Cyclooxygenase 2 (COX-2) Expression During Malignant Melanoma Progression , 2003, Cancer biology & therapy.