Circ_PABPC1 promotes the malignancy of gastric cancer through interacting with ILK to activate NF-κB pathway

As one of the most common malignant tumors, the incidence and mortality of gastric cancer (GC) are ranked at the fifth and the second places among the 36 types of cancer around the world, respectively [1,2]. Approximately 50 % of patients with GC come from East Asia, mainly from China [3]. Long-term intake of high-salt food, smoking and obesity have been considered to be risk factors for GC ([4]; Yusefi et al., 2018). Although great progress has been made in the diagnosis and treatment of GC in recent years, many patients with GC still suffer from short survival time and poor prognosis [5]. It is of vital importance to unveil the molecular mechanisms underlying pathogenesis of GC and identify effective diagnostic markers and drug targets to improve the survival of GC patients [5,6].

Circular RNA (circRNA) is a type of noncoding RNA expressed in eukaryotic cells [6], in which the 5′ and 3’ ends were covalently linked to form a circular RNA [7]. With the development of RNA sequencing technology, more and more circRNAs have been found [1,8,9]. Previous studies have shown that circRNA plays an important role in the occurrence and development of GC [10]. For example, circ_OSBPL10, circ_006100 and circ_SERPINE2 have been proved to promote the proliferation, invasion and migration of GC cells [11,12]. Hsa_circ_002059 has been found to be significantly downregulated in GC, and its expression level is related to distant metastasis and TNM stage of gastric cancer [13,14]. In particular, the expression level of has_circ_002059 in plasma samples of GC patients after operation is significantly higher than that before operation, suggesting that it is a potential biomarker of GC prognosis [13]. Furthermore, Jie Chen et al. has found that the expression of circPVT1 is up-regulated in GC. circPVT1 competitively combines with the members of miR-125 family, resulting in enhanced proliferation of GC cells [15]. Therefore, the role of circular RNA in the initiation and progression of GC is indeed important, while mechanism by which a specific circular RNA regulates the growth properties of GC is needed to be studied further.

Apart from acting as “sponges” of miRNA to regulate mRNA expression [16,17], circRNA regulates various cellular processes through acting as protein sponges, protein traps, protein scaffolds, protein recruiters via direct interaction with proteins [18]. RNA-binding proteins (RBPs) including Argonaute (AGO) and muscleblind (MBL) have been found to bind to circRNAs [16,19,20]. Particularly, the biosynthesis of circMBL affects the alternative splicing of MBL mRNA [19]; circ-PABPN1 has been reported to competitively bind to HuR, inhibiting HuR from enhancing translation of PABPN1 [21]. The circRNA-protein interactions may be highly common [18], and further studies are needed to elucidate the effect on the function of proteins after the circRNA-protein interaction.

Integrin-linked kinase (ILK) is an important effector in integrin and growth factor receptor signal transduction pathway. It has a variety of biological functions in the regulation of cell proliferation, differentiation, growth, adhesion, migration, infiltration and tumor angiogenesis [22,23]. ILK is lowly expressed in normal human tissues, but highly expressed in tumor tissues including neurogenic tumors, lung cancer, melanoma, ovarian cancer, prostate cancer, GC and colon cancer [[24], [25], [26], [27]]. ILK expression level gradually increased with the increase of tumor pathological grade, therefore its expession level is significantly related to the malignant degree and metastasis of multiple cancers [27]. Ito et al. have reported that ILK is expressed at a low level in normal gastric mucosa, but highly expressed in GC [28]. It has also been reported that the expression of ILK is significantly correlated with the differentiation, invasion depth and clinical stage of GC [29].

The nuclear factor-κB (NF-κB) is a transcription factor expressed in a variety of solid tumors, which mainly regulates inflammation and autoimmune responses [30,31]. A few of studies have found that NF-κB plays an important role in controlling carcinogenesis and metastasis, through regulating cell cycle and apoptosis and affecting cell differentiation process [[32], [33], [34]]. It has been shown that NF-κB is involved in the regulation of GC by regulating the expression of downstream factors of NF-κB signaling pathway [35,36].

In this study, we analyzed the public high-throughput RNA sequencing data provided by GEO database to search of candidate circRNA molecules, and validated their expression in GC tissues and adjacent tissues. Circ_PABPC1 attracted our attention in this study. The PABPC1 protein derived from PABPC1-mRNA has been reported to regulate cancer development [37]. However, the role and mechanism of circ_PABPC1 in GC have not been reported. This study explored the molecular mechanism of circ_PABPC1 in the regulation of GC progression, and provided a new target for developing targeted therapy in patients with GC.

留言 (0)

沒有登入
gif