SPARC Promotes Cathepsin B-Mediated Melanoma Invasiveness through a Collagen I/α2β1 Integrin Axis

Abstract

In melanoma, the extracellular protein SPARC (secreted protein acidic and rich in cysteine) is related to tumor progression. Some of the evidence that links SPARC to melanoma progression indicates that SPARC may be involved in the acquisition of mesenchymal traits that favor metastatic dissemination. However, no molecular pathways that link extracellular SPARC to a mesenchymal phenotype have been described. In this study, global protein expression analysis of the melanoma secretome following enforced downregulation of SPARC expression led us to elucidate a new molecular mechanism by which SPARC promotes cathepsin B-mediated melanoma invasiveness using collagen I and α2β1 integrins as mediators. Interestingly, we also found that the transforming growth factor (TGF)-β1 contribution to cathepsin B-mediated invasion is highly SPARC dependent. In addition, induction of the E-cadherin to N-cadherin switch by SPARC enabled melanoma cells to transmigrate across an endothelial layer through a mechanism independent to that of enhancing invasion. Finally, SPARC also enhanced the extracellular expression of other proteins involved in epithelial-mesenchymal transformation, such as family with sequence similarity 3, member C/interleukin-like EMT-inducer. Our findings demonstrate a previously unreported molecular pathway for SPARC activity on invasion and support an active role of SPARC in the mesenchymal transformation that contributes to melanoma dissemination.

Integrin β4 Regulates SPARC Protein to Promote Invasion

“…This role for SPARC is supported by the findings that SPARC can promote cell motility and invasion in various carcinoma cells, including breast (53)(54)(55)(56)(57)(58)(59)(60). Moreover, SPARC expression has been associated with basal-like breast cancers (61).…”

Mitofusin-2 over-expresses and leads to dysregulation of cell cycle and cell invasion in lung adenocarcinoma

“…RAP1A has been implicated in cell adhesion and junction formation [31], while RALB is involved in the proliferation, survival and metastasis of variant cancers [32]. ITGA2, the alpha subunit of collagen receptor, has been implicated in cell adhesion and migration [33]. The quite opposite functions of MFN2 on different oncogenes might be account for the paradoxical findings about MFN2 roles in cancer development by us and other laboratories, as it is possible that the overall impact of MFN2 on oncogenes might be different or even opposite depending on the environmental conditions and cancer types.…”

Targeting SPARC by lentivirus-mediated RNA interference inhibits cervical cancer cell growth and metastasis

“…Although there is growing evidence for an important role for SPARC in a variety of cancers, there is no unifying model, which explains all aspects of its function [9,11]. For example, higher levels of SPARC expression have been reported in breast cancer [12,13], melanoma [14,15], hepatocellular carcinoma [16,17], prostate cancer [18] and colorectal cancer [19,20]. However, the opposite effect has also been demonstrated, suggesting that SPARC may be able to inhibit tumorigenesis or tumor progression in breast cancer [21,22], ovarian carcinoma [23,24], hepatocellular carcinoma [25], prostate cancer [26], and colorectal cancer [27,28].…”