Soares Ciro D, Borges Camilla F, Sena-Filho Marcondes, Almeida Oslei P de, Stelini Rafael F, Cintra Maria L, Graner Edgard, Zecchin Karina G, Jorge Jacks
aUnit of Oral Pathology, Department of Oral Diagnosis, Piracicaba Dental School bDepartment of Pathology, Medical Sciences School, University of Campinas, Campinas, Brazil.
Melanoma Res. 2017 Oct;27(5):448-456. doi: 10.1097/CMR.0000000000000368.
Cyclooxygenase 2 (COX-2) and phosphorylated Akt1 (p-Akt1) are associated with tumor spreading, cell proliferation, high metabolism, and angiogenesis in solid tumors. This study aimed to investigate COX-2 and p-Akt1 expression in primary and metastatic melanomas by correlating with the cellular proliferation index (as revealed by minichromosome maintenance 2 expression) and the outcome of patients with malignant melanomas. Seventy-seven biopsies of malignant melanomas, including 42 primary nonmetastatic melanomas (PNMMs), 12 primary metastatic melanomas (PMMs), and 23 metastatic melanomas (MMs), were retrospectively selected. Tissue microarrays were developed and submitted for immunohistochemical staining for COX-2, p-Akt1, and minichromosome maintenance 2. Increased COX-2 cytoplasmic staining patterns were observed in PMM and MM when compared with PNMM (P=0.0011). Higher nuclear and cytoplasmic expression of p-Akt1 was more closely associated with PMM than with MM and PNMM (P<0.00001). Coexpression of these biomarkers was closely correlated with lower overall survival rates in melanomas. Furthermore, we observed a statistically significant positive correlation between the mitosis index and increased COX-2 expression (P=0.0135) and between p-Akt1 (P=0.0038) and the cellular proliferation index (P=0.0060). Taken together, our findings demonstrate that COX-2 and p-Akt1 play an important combined role during melanoma progression and are associated with highly metastatic tumors and survival rates in patients with MM. In addition, these biomarkers can be used to predict melanoma prognosis independently of metastatic status. However, further studies are required to elucidate the biological role of these biomarkers during the progression of MM events.
环氧化酶2（COX-2）和磷酸化Akt1（p-Akt1）与实体瘤的肿瘤扩散、细胞增殖、高代谢及血管生成相关。本研究旨在通过与细胞增殖指数（以微小染色体维持蛋白2表达显示）及恶性黑色素瘤患者的预后相关联，来探究COX-2和p-Akt1在原发性和转移性黑色素瘤中的表达情况。回顾性选取了77例恶性黑色素瘤活检样本，包括42例原发性非转移性黑色素瘤（PNMM）、12例原发性转移性黑色素瘤（PMM）和23例转移性黑色素瘤（MM）。制作组织微阵列，并进行COX-2、p-Akt1和微小染色体维持蛋白2的免疫组化染色。与PNMM相比，PMM和MM中观察到COX-2胞质染色模式增加（P = 0.0011）。p-Akt1的核和胞质高表达与PMM的相关性比与MM和PNMM的更紧密（P < 0.00001）。这些生物标志物的共表达与黑色素瘤较低的总生存率密切相关。此外，我们观察到有丝分裂指数与COX-2表达增加之间存在统计学显著正相关（P = 0.0 | 135），以及p-Akt1（P = 0.0038）与细胞增殖指数之间存在统计学显著正相关（P = 0.0060）。综上所述，我们的研究结果表明，COX-2和p-Akt1在黑色素瘤进展过程中发挥重要的联合作用，且与高转移性肿瘤及MM患者的生存率相关。此外，这些生物标志物可独立于转移状态用于预测黑色素瘤预后。然而，需要进一步研究以阐明这些生物标志物在MM事件进展过程中的生物学作用。
