Overexpression of autophagy-related beclin-1 in advanced malignant melanoma and its low expression in melanoma- in-situ

ARTICLE

ejd.2011.1562

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

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

Autophagy is an intracellular pathway for the self-catabolic process that maintains intracellular homeostasis and prolongs cell survival under stresses like oxygen and nutrient depletion, via lysosomal degradation of cytoplasmic constituents and recycling of amino acids and energy [1-3]. 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), which engulf organelles and cytoplasm then fuse with the lysosome to form the autolysosome, where the contents are degraded and recycled for protein and ATP. Autophagosome formation is mediated by a number of proteins, including beclin-1 (BECN-1), a part of the lipid kinase complex. In this study, we examined BECN-1 expression by immunohistochemistry in 5 samples of advanced malignant melanoma (MM) more than 2 mm in thickness and in 3 specimens of MM in situ.

Histopathological analysis of the tumor on the lateral left sole of a 65-year-old female showed proliferation of highly atypical cells with hyperchromatic pleomorphic nuclei, leading to a diagnosis of malignant melanoma (figure 1A). Tumor thickness was 3.5mm and a sentinel inguinal lymph node biopsy was also positive for tumor cells. Immunohistochemical study using an anti-BECN-1 antibody (Santa Cruz, Santa Cruz, CA) revealed that tumor cells were strongly positive for BECN-1 (figure 1B). All the five samples of advanced MM more than 2mm in thickness (>T3) expressed BECN-1 strongly.

Histopathology of a black macule, 15 × 15mm, on the left 5^th toe of a 61-year-old female revealed a sparse proliferation of atypical cells with hyperchromatic and occasionally pleomorphic nulei only within the epidermis, leading to a diagnosis of acral lentiginous MM in situ (figure 1C). A sentinel lymph node biopsy was negative for tumour cells. Immunohistochemical study showed that tumor cells expressed BECN-1 weakly (figure 1D). All the 3 samples of MM in situ examined in this study were weakly positive for BECN-1.

In summary, all 5 samples from advanced MM more than 2 mm in thickness (>T3) were strongly positive for BECN-1, while all 3 melanoma-in-situ samples expressed BECN-1 weakly. Recently, we reported that BECN-1 was highly expressed in large squamous cell carcinoma (SCC) and SCC with lymph node metastasis [4]. Our results in this study indicate that autophagy may be activated in both advanced SCC and MM.

Armstrong et al. demonstrated a pro-survival function of autophagy in MM [5]. They used endoplasmic reticulum (ER) stress-inducing drugs, feneretinide and bortezomib. Autophagy was activated in response to feneretinide and bortezomib, however, knockdown of autophagy-related BECN-1 or ATG7 (autophagy-related 7 homolog) sensitized MM cells to fenretinide- or bortezomib-induced cell death, suggesting that autophagy plays an important role in the survival of MM cells.

BECN-1 has also been proposed to regulate angiogenesis in MM using mouse melanoma tumour models [6]. Proliferation, migration and tube formation in response to hypoxia were altered in BECN-1 hemizygous deficient mice. Hypoxia-inducible factor-2α (HIF-2α) was reported to be responsible for these changes. Therefore, high expression of BECN-1 in advanced MM may regulate not only the proliferation of MM cells but also angiogenesis changes in MM. Knockdown of BECN-1 may be a new therapeutic approach for advanced MM.

Disclosure

Financial support: none. Conflicts of interest: none.

References

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