LIN28B Underlies the Pathogenesis of a Subclass of Ewing Sarcoma

Abstract

Ewing sarcoma (EwS) is associated with poor prognosis despite current multimodal therapy. Targeting of EWS-FLI1, the fusion protein responsible for its pathogenesis, and its principal downstream targets has not yet produced satisfactory therapeutic options, fueling the search for alternative approaches. Here, we show that the oncofetal RNA-binding protein LIN28B regulates the stability of EWS-FLI1 mRNA in~10% of EwSs. LIN28B depletion in these tumors leads to a decrease in the expression of EWS-FLI1 and its direct transcriptional network, abrogating EwS cell self-renewal and tumorigenicity. Moreover, pharmacological inhibition of LIN28B mimics the effect of LIN28B depletion, suggesting that LIN28B sustains the emergence of a subset of EwS in which it also serves as an effective therapeutic target.

Hsa_circ_0002137 stabled by LIN28B promotes osteosarcoma cell growth through the hsa-miR-1246/BCL2 axis

“…For example, lncRNA NEAT1 is stabilized by LIN28B protein in ovarian cancer (Wu et al, 2018). Similarly, LIN28B increases EWS-FLI1 mRNA stability in Ewing sarcoma (Keskin et al, 2020). However, whether LIN28B regulates circRNA stability remains an open question.…”

Preeclampsia: Cardiotonic Steroids, Fibrosis, Fli1 and Hint to Carcinogenesis

“…When levels of MBG are increased, levels of Fli1 decrease and a Col-1 gene promoter is released from the nucleus and procollagen-1 and collagen become activated [32]. While many studies have demonstrated that Fli1 is a pro-cancer factor [68,69], CS including MBG are becoming attractive anti-cancer drug candidates [70,71]. It is generally accepted that PE is associated with a low risk of cancer, which is not surprising considering that endogenous levels of MBG and other CS are dramatically increased in PE patients [27,28] and therefore suppress the growth of tumors in vivo and in vitro [72][73][74].…”

Preeclampsia: Сardiotonic Steroids, Fibrosis and a Hint to Cancerogenesis

“…When levels of MBG are increased, levels of Fli1 decrease, and Col-1 gene promoter is released from the nucleus, and pro-collagen-1 and collagen become activated [32]. While many studies demonstrate that Fli1 is a pro-cancer factor [57,58], CS, including MBG, are becoming attractive anticancer drugs [59,60]. It is generally accepted that PE is associated with a low risk of cancer, which is not surprising considering that endogenous levels of MBG and other CS are dramatically increased in PE patients [27,28] and therefore suppress the growth of tumors in vivo and in vitro [61,62,63].…”

“…This phenotype was consistent with a role of Fli1 as a regulator of vessel maturation, thus, in rats following subtotal nephrectomy, elevated MBG led to a reduction in the level of Fli1 and an increase in collagen-1 level in the myocardium, and single administration of monoclonal anti-MBG antibody rats produced an antifibrotic effect, that is, restored Fli1 levels and reduced collagen-1 abundance in the myocardium [38]. Fli1 attracted attention primarily because of its contribution to different types of cancer including, gastric cancer, Burkitt lymphoma, breast cancer, pancreatic ductal adenocarcinoma, small cell lung cancer, and Ewings sarcoma [57,74,75,76]. We observed extremely high levels of MBG, low levels of Fli1, along with a very extremely high level of collagen-1 level in patients and experimental animals with preeclampsia, chronic renal failure, and malignant hypertension [33,37,38].…”