Abstract
Simple SummaryAmplification and overexpression of the SEC62 oncogene was reported in a variety of human cancers and was associated with poor prognosis as well as lymph node and distant metastases. In this study, SEC62 expression was analyzed in benign, borderline, and malignant melanocytic lesions of 209 patients. We found the highest expression in Spitz nevi, followed by melanoma metastases, primary melanoma, congenital nevi, and blue nevi. In melanoma patients, high Sec62 levels correlated with shorter overall and progression-free survival. Significantly higher Sec62 levels were found in melanomas with lymph node and distant metastases compared with those without. Taken together, these data suggest a relevant role of SEC62 as a metastasis-stimulating oncogene in melanoma development, which represents a promising therapeutic target.SEC62 oncogene located at chromosomal region 3q26 encodes for a transmembrane protein of the endoplasmic reticulum (ER) and is expressed at high levels in numerous human malignancies. SEC62 overexpression has been associated with worse prognosis and high risk for lymphatic and distant metastases in head and neck cancer, cervical cancer, hepatocellular cancer, and lung cancer. However, its role in the development and tumor biology of melanocytic lesions has not been investigated so far. An immunohistochemical study including 209 patients with melanocytic lesions (malignant melanoma (MM), n = 93; melanoma metastases (MET), n = 28; Spitz nevi (SN), n = 29; blue nevi (BN), n = 21; congenital nevi (CN), n = 38) was conducted and SEC62 expression was correlated with clinical data including patient survival and histopathological characteristics. SN showed the highest SEC62 expression levels followed by MET, MM, CN, and BN. High SEC62 expression correlated with a shorter overall and progression-free survival in MM patients. Additionally, high Sec62 levels correlated significantly with higher tumor size (T stage), the presence of tumor ulceration, and the presence of lymph node as well as distant metastases. Strikingly, SEC62 expression showed a strong correlation with Clark level. Taken together, these data demonstrate that SEC62 is a promising prognostic marker in MM and has the potential to predict biological behavior and clinical aggressiveness of melanocytic lesions.
Highlights
The SEC62 gene located at the long arm of chromosome 3 (3q26.2) encodes for a transmembrane protein of the endoplasmic reticulum (ER) and is a component of the human Sec complex, which is responsible for the translocation of precursor proteins from the cytosol into the endoplasmic reticulum (ER) lumen, as well as the regulation of intracellular calcium homeostasis
Amplification of the 3q26 region and overexpression of the SEC62 gene have been found in several cancer entities over the past decades including head and neck squamous cell carcinomas (HNSCC) [10,11], prostate cancer [12], esophageal cancer [13], cervical cancer [14,15], ovarian cancer [16], breast cancer [17], and non-small cell lung cancer (NSCLC) [18]
When correlating SEC62 expression level with different clinical and histopathological features in melanoma, including T, N, and M stages; the presence of ulceration; sex; localization of primary tumor; and MM subtype, we found significantly higher Sec62 levels in patients with lymph node or distant metastases in comparison
Summary
The SEC62 gene located at the long arm of chromosome 3 (3q26.2) encodes for a transmembrane protein of the endoplasmic reticulum (ER) and is a component of the human Sec complex, which is responsible for the translocation of precursor proteins from the cytosol into the endoplasmic reticulum (ER) lumen, as well as the regulation of intracellular calcium homeostasis. Beneath its potential role as a prognostic biomarker in the aforementioned cancer entities, Sec directly influences tumor cell biology by stimulating cancer cell migration and invasion, as well as enabling tumor cells to recover from ER stress through a molecular mechanism called recovER-phagy [8,24,25,26,27,28]. These effects can explain how tumor cells profit from an increased SEC62 expression level and might be responsible for the poor prognosis of SEC62-overexpressing tumors. The exact molecular mechanisms of how Sec can influence tumor cell migration and invasion through a regulation of cytosolic calcium levels remain elusive
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