Thrombospondin-1, an extracellular matrix protein, is the first identified natural angiogenesis inhibitor. Thrombospondin-1 participates in a great number of physiological and pathological processes, including cell-cell and cell-matrix interactions via a number of cell receptors, including CD36 and CD47, which plays a vital role in mediating inflammation and performs a promoting effect in pulmonary arterial vasculopathy and diabetes. Thrombospondin-1 consists of six domains, which combine with different molecules and participate in various functions in cancers, serving as a critical member in diverse pathways in cancers. Thrombospondin-1 works as a cancer promotor in some pathways but as a cancer suppressor in others, which makes it highly possible that its erroneous functioning might lead to opposite effects. Therefore, subdividing the roles of thrombospondin-1 and distinguishing them in cancers are necessary. Complex structure and multiple roles take disadvantage of the research and application of thrombospondin-1. Compared with the whole thrombospondin-1 protein, each thrombospondin- 1 active peptide performs an uncomplicated structure and, nevertheless, a specific role. In other words, various thrombospondin-1 active peptides may function differently. For instance, thrombospondin-1 could both promote and inhibit glioblastoma, which is significantly inhibited by the three type I repeats, a thrombospondin-1 active peptide but promoted by the fragment 167-569, a thrombospondin-1 active peptide consisting of the procollagen homology domain and the three type I repeats. Further studies of the functions of thrombospondin-1 active peptides and applying them reasonably are necessary. In addition to mediating cancerogenesis, thrombospondin-1 is also affected by cancer development, as reflected by its expression in plasma and the cancer tissue. Therefore, thrombospondin-1 may be a potential biomarker for pre-clinical and clinical application. This review summarizes findings on the multiple roles of thrombospondin-1 in cancer processes, with a focus on its use as a potential therapeutic target.

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Ovarian Clear Cell Carcinoma (OCCC) displays distinctive clinical and molecular characteristics and confers the worst prognosis among all ovarian carcinoma histotypes when diagnosed at advanced stage, because of the lack of effective therapy. IGF2BP3 is an RNA binding protein that modulates gene expression by post-transcriptional action. In this study, we investigated the roles of IGF2BP3 in the progression of OCCC. We used 328 OCCCs from the AOVT (the Alberta Ovarian Tumor Type study) and the COEUR (the Canadian Ovarian Experimental Unified Resource) cohorts to elucidate the associations between IGF2BP3 expression and clinicopathological parameters, with positive IGF2BP3 expression defined as diffuse block staining, being more frequently observed at stage III (P = 0.0056) and significantly associated with unfavorable overall survival (HR = 1.59, 95% CI 1.09-2.33) in multivariate analysis. IGF2BP3 mRNA gene expression was markedly increased in OCCC cell lines compared to normal tissues such as ovarian surface epithelium. We chose two IGF2BP3-overexpressing cell lines ES2 and OVMANA for in vitro and in vivo knockdown experiments. The proliferation and viability of both cell lines were significantly inhibited by two IGF2BP3 siRNAs and similar suppression was observed in cell migration and invasion by Wound Healing and Transwell assays. The percentage of apoptotic cancer cells was enhanced by both IGF2BP3 siRNAs. In vivo experiments showed significantly reduced sizes of tumors when treated with IGF2BP3 siRNA compared to controls. Furthermore, cancer metastasis-indicators MMP2 and MMP9 proteins were down-regulated. In conclusion, our study shows that IGF2BP3 expression is a promising biomarker for prognostication of women diagnosed with OCCC with multiple effects on key cell functions, supporting its role as an important cellular regulator with potential oncogenic activity, and as a potential target for future intervention strategies.