Abstract
Tetraspanins CD9 and CD81 frequently serve as the surface markers of exosomes, which are involved in intercellular communication during tumor progression. KLF4 is a well-known tumor suppressor in various cancers. This study aims to investigate the relationship between KLF4 and CD9/CD81 in hepatocellular carcinoma (HCC). The results showed that CD9 and CD81 were transcriptionally activated by KLF4 in HCC cell lines. Decreased expressions of CD9 and CD81 were found in most HCC tumor tissues and predicted advanced stages. Furthermore, KLF4 expression was positively associated with CD9 and CD81 expression in HCC specimens. Functionally, overexpression of CD9 and CD81 inhibited HCC cell proliferation in vitro and in vivo and silencing CD9 and CD81 displayed opposite phenotypes. Mechanistically, we found that JNK signaling pathway may be involved in the growth suppression mediated by CD9 and CD81. In addition, increased expression of KLF4, CD9 or CD81 had no obvious impact on exosome secretion from HCC cells. Collectively, we identified CD9 and CD81 as new transcriptional targets of KLF4 and the dysregulated KLF4-CD9/CD81-JNK signaling contributes to HCC development. Our findings will provide new promising targets against this disease.
Highlights
Exosome, a major component of extracellular vesicles (EVs), is a nanometer-sized membrane structure ranging in diameter from 30 to 150 nm, which could be secreted by most cell types[1]
To elucidate whether Krüppel-like factor 4 (KLF4) has a link with these exosomal surface markers, we firstly examined the expression of these proteins after overexpression of KLF4 in hepatocellular carcinoma (HCC) cell lines
The western blot results indicated that KLF4 overexpression significantly enhanced CD9 and CD81 expression in L02 and Huh[7] cells, while no obvious change were observed in the levels of CD63, Alix, and TSG101 (Fig. 1a)
Summary
A major component of extracellular vesicles (EVs), is a nanometer-sized membrane structure ranging in diameter from 30 to 150 nm, which could be secreted by most cell types[1]. A number of reports have demonstrated that exosomes participate in cell–cell communications in both physiological activities and pathological changes by transferring differential cargos, including proteins, DNAs, microRNAs, lncRNAs, and mRNAs2–4. Exosome-mediated transfer has been shown to contribute to tumor cell proliferation, metastasis, and signal transduction[5,6,7]. Exosomes are commonly characterized by unique surface proteins including the tetraspanins (CD9, CD63, CD81, etc.) and other molecules (intergrins, Alix, Tsg[101], etc.)[13,14,15]. The tetraspanins CD9 and CD151 have been reported to enhance the migration and invasion abilities of prostate cells, which suggest that exosomal tetraspanins might act as a driver of metastasis in prostate cancer[16]
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