Overexpression of autophagy-related beclin-1 in cutaneous squamous cell carcinoma with lymph-node metastasis

ARTICLE

ejd.2011.1516

Auteur(s) : Risa Okura, Motonobu Nakamura motonaka@med.uoeh-u.ac.jp

Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka Yahatanishi-ku, Kitakyushu 807-8555, Japan

Autophagy is a self-catabolic process that maintains intracellular homeostasis and prolongs cell survival under stress via lysosomal degradation of cytoplasmic constituents and recycling of amino acids and energy [1]. Autophagy plays a dual role in tumorigenesis, acting both as a protector of cancer cell survival and a tumor suppressor. The process of autophagy involves the formation of double-membrane vesicles (autophagosomes) that engulf organelles and cytoplasm, then fuse with the lysosome to form the autolysosome, where the contents are degraded and recycled for protein and ATP. The formation of the autophagosome is mediated by a number of proteins, including beclin-1 (BECN1), part of the lipid kinase complex. In this study, we examined BECN1 expression in 10 specimens of cutaneous squamous cell carcinoma (SCC), by immunohistochemistry.

A 78-year-old male visited our hospital due to a tumor on the scrotum, which had enlarged gradually for two years. Physical examination revealed a dome shaped tumor on the ventral scrotum, 18 mm in diameter (figure 1A). The tumor was resected under general anesthesia and histopathological analysis of the tumor specimen showed atypical squamous cells with hyperchromatic and occasionally pleomorphic nuclei arranged in a sheet-like growth pattern with focal keratinization, leading to a diagnosis of SCC (figure 1B). Although the surgical margin was histopathologically free of tumor cells and inguinal lymph nodes were not palpable at the time of surgery, the left inguinal lymph node grew rapidly two years after the initial resection. Histological examination of a lymph node biopsy revealed accumulating atypical squamous cells with pleomorphic nuclei, leading to a diagnosis of lymph node metastasis of squamous cell carcinoma. Due to a rapid enlargement of the lymph node and the patient's reluctance to undergo surgery, we performed a radio therapy for the lymph node and it diminished in size after 60 Gy irradiation.

To examine the expression levels of BECN1 in the tumor and lymph node, we used an anti-BECN1 antibody (Santa Cruz, Santa Cruz, CA) for immunohistochemistry. Both SCC cells and lymph node-metastasized cells expressed BECN1 highly (figure 1C, D), while no, or faint, BECN1 expression could be observed in peritumoral epidermis, hair follicles and eccrine sweat glands. We further investigated other 9 patients with SCC. All 3 SCC patients with lymph node metastasis showed high immunoreactivity for BECN1, however, 6 out of 7 SCC patients without apparent lymph node metastasis expressed BECN1 very little. Lymph nodes of all 3 SCC patients also expressed BECN1 highly. The sizes of 4 SCC tumors with high BECN1 expression (two females and two males, age: 56-78) were significantly larger in diameter (40.8±25.2 mm) than 6 SCC tumors with low BECN1 expression (three females and three males, age: 74-94, 10.3±4.0 mm).

Taken together, BECN1 was highly expressed in large SCC and SCC with lymph node metastasis. In cases of esophageal squamous cell carcinoma, BECN1 expression significantly correlated with depth of invasion, lymph node metastasis and clinical stage [2]. In general, starvation-induced autophagy is accompanied with suppression of protein synthesis, cell division and motility in an energy conservation effort that results in autophagy-mediated support of tumor cell survival [1]. Our results indicate that BECN1 and autophagy plays an important role in controlling the development and progression of cutaneous SCC and BECN1 expression level may be a prognostic predictor of clinical outcome in patients with cutaneous SCC.

Disclosure

Financial support: none. Conflicts of interest: none.

References

1. Chen N, Karantza V. Autophagy as a therapeutic target in cancer. Cancer Biol Ther 2011 ; 11 : 157-168.

2. Chen Y, Lu Y, Lu C, Zhang L. Beclin-1 expression is a predictor of clinical outcome in patients with esophageal squamous cell carcinoma and correlated to hypoxia-inducible factor (HIF)-1a expression. Pathol Oncol Res 2009 ; 15 : 487-493.