Melanoma tumors frequently acquire LRP2/megalin expression, which modulates melanoma cell proliferation and survival rates

Abstract

Subscribe to PCMR and stay up-to-date with the only journal committed to publishing basic research in melanoma and pigment cell biology As a member of the IFPCS or the SMR you automatically get online access to PCMR. Sign up as a member today at www.ifpcs.org or at www.societymelanomaresarch.org If you wish to order reprints of this article, please see the guidelines here Submit your next paper to PCMR online at http://mc.manuscriptcentral.com/pcmr Summary We show that the multiligand receptor megalin, known to mediate uptake and trafficking of nutrients and signaling molecules, is frequently expressed in malignant melanoma samples. Expression of megalin-encoding mRNA was investigated in 65 samples of nevi, melanomas, and melanoma metastases and was observed in more than 60% of the malignant samples, while only in 20% of the benign counterparts. Megalin expression in nevus and melanoma samples was additionally investigated by immunohistochemistry, which confirmed our mRNA-based observations. We furthermore show that a panel of tumor-derived melanoma cell lines express LRP2/megalin endogenously. In these cells, megalin is internalized from the cell surface and localizes extensively to intracellular vesicles, confirming receptor activity and pointing toward association with the endocytic apparatus. Groundbreaking, our results indicate that sustained megalin expression in melanoma cells is crucial for cell maintenance, as siRNA-mediated reduction in melanoma cell expression of LRP2/megalin significantly decreases melanoma cell proliferation and survival rates.

Megalin Is Predominantly Observed in Vesicular Structures in First and Third Trimester Cytotrophoblasts of the Human Placenta

“…52 The IGF-1 and EGF growth factors known to promote placental development and growth as well as fetal growth 5 are both established ligands for megalin, 15,16 and a recently published study of megalin function in melanoma cells revealed that megalin may be involved in modulation of IGF-1 signaling in these cells. 26 In the context of growth factor signaling, MVBs were previously shown to play key roles in the control of growth factor signaling (e.g., EGF signaling), 53 and interestingly, we observed megalin on the luminal vesicles of MVBs as well as their outer limiting membrane in cytotrophoblasts of first trimester and term placenta. To our knowledge, megalin has not previously been identified in MVBs.…”

“…7A, term placenta megalin and JAR cellderived megalin were both recognized by the purified anti-megalin antibody previously used for studies of human renal and melanoma megalin. [24][25][26] Also, the molecular weight of term placenta megalin and JAR cell-derived megalin was similar to that of renal megalin (Fig. 7A).…”

“…We think they may be a result of differences in antibody specificity, tissue preparation, section thickness, and/or the immunohistochemical method applied. For the present study of megalin in human placenta, we used Editor's Highlight a well-characterized, [24][25][26] protein G-purified rabbit polyclonal antibody raised against ligand affinity-purified human megalin. Most importantly, the specificity of the antibody has been verified on renal tissue from patients lacking the megalin protein.…”

“…The polyclonal rabbit anti-human megalin antibody used in this study is well characterized [24][25][26] and was a kind gift from Dr. Soren K. Moestrup, Aarhus University, Denmark. Protein G-purified rabbit anti-human megalin antibody was used (immunofluorescence: 10 µg/ ml; IHC: 6.60-8.25 µg/ml; immunocytochemistry: 1.65 µg/ml …”

Cancer stem cell associated eight gene‑based signature predicts clinical outcomes of colorectal cancer

“…LRP2 is a component and an auxiliary Hedgehog signaling receptor (30). Andersen et al (31) reported that LRP2 regulated melanoma cell proliferation and survival rates, and that knocking down LRP2 induced apoptosis. LRP2 may serve a similar function in colorectal cancer.…”