Hairong Xiong,Jiaxin Ye,Qianqian Luo,Wen Li,Ning Xu,Hongmei Yang
Cancer cachexia is a systemic inflammation-driven syndrome, characterized by muscle atrophy and adipose tissue wasting, with progressive weight loss leading to serious impairment of physiological function. Extracellular vesicles (EVs) derived from cancer cells play a significant role in adipocyte lipolysis, yet the mechanism remain uneclucidated. In this study, EVs derived from Lewis lung carcinoma (LLC) cells were extracted and characterized. 3 T3-L1 and HIB1B adipocytes were cultured with conditioned medium or EVs from LLC, and LLC cells were used to establish a cancer cachexia mouse model. EVs derived from LLC cells were taken up by 3 T3-L1 and HIB1B adipocytes, and derived exosomal EIF5A protein-induced lipolysis of adipocytes. High level of EIF5A was expressed in EVs from LLC cells, exosomal EIF5A is linked to lipid metabolism. Elevated expression of EIF5A is associated with shorter overall survival in lung cancer patients. Western blots, glycerol release and Oil red O staining assays were used to evaluate lipolysis of adipocytes. The reduction of lipolysis in 3 T3-L1 and HIB1B adipocytes is achieved through silencing EIF5A or treating with pharmacologic inhibitor GC7 in vitro, and suppressing the expression of EIF5A in LLC cells by infected with shRNA or GC7 treatment partly alleviated white and brown adipose tissue lipolysis in vivo. Mechanistically, EIF5A directly binds with G protein-coupled bile acid receptor 1 (GPBAR1) mRNA to promote its translation and then activates cAMP response element binding protein (CREB) signaling pathway to induce lipolysis. This study demonstrates that exosomal EIF5A from LLC cells, with hypusinated EIF5A, has a lipolytic effect on adipocyte and adipose tissues in cancer cachexia model. Exosomal EIF5A could be involved in lipolysis and these findings indicate that a novel regulator and potential target for cachexia treatment.
Cervical cancer (CC) is the most common human papillomavirus‑related disease. Continuous activation of the NF‑κB signaling pathway has been observed in CC. SHC binding and spindle associated 1 (SHCBP1) contributes to tumorigenesis and activation of the NF‑κB pathway in multiple cancer types, while its function in CC remains unclear. In the present study, three Gene Expression Omnibus datasets were used to identify differentially expressed genes (DEGs) in CC. Loss‑ and gain‑of‑function experiments were performed using stable SHCBP1‑silenced and SHCBP1‑overexpressing CC cells. To further explore the molecular mechanism of SHCBP1 in CC, small interfering RNA targeting eukaryotic translation initiation factor 5A (EIF5A) was transfected into stable SHCBP1‑overexpressing CC cells. The results demonstrated that SHCBP1 was an upregulated DEG in CC tissues compared with healthy control cervical tissues. Functional experiments revealed the pro‑proliferative and pro‑stemness role of SHCBP1 in CC cells (CaSki and SiHa cells), in vitro. Furthermore, the NF‑κB signaling pathway in CC cells was activated by SHCBP1. Increases in cell proliferation, stemness and activation of NF‑κB, induced by SHCBP1 overexpression in CC cells, were reversed by EIF5A knockdown. Taken together, the results indicated that SHCBP1 serves an important role in regulation of CC cell proliferation, self‑renewal and activation of NF‑κB via EIF5A. The present study demonstrated a potential molecular mechanism underlying the progression of CC.
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