The RNA-binding protein PCBP2 facilitates gastric carcinoma growth by targeting miR-34a
Introduction
Gastric cancer is the fourth most common cancer worldwide, with a high rate of death and low 5-year survival rate [1]. Despite extensive research to identify novel diagnostic and therapeutic agents, patients with advanced gastric cancer suffer from a poor quality of life and poor prognosis, and treatment is dependent mainly on conventional cytotoxic chemotherapy [2]. To improve the quality of life and survival of gastric cancer patients, a better understanding of the underlying molecular mechanisms, and their application towards the development of novel targeted therapies, is urgently needed.
Poly(C)-binding proteins (PCBPs) are generally known as RNA-binding proteins that interact in a sequence-specific fashion with single-stranded poly(C). This family can be divided into two groups: hnRNP K and PCBP1-4. PCBPs are expressed broadly in human and mouse tissues and all members of the PCBP family are related evolutionarily. These proteins are involved mainly in various posttranscriptional regulations (e.g., mRNA stabilization or translational activation/silencing) [3]. It has been suggested that PCBPs play a critical role in carcinogenesis. hnRNP K induces transcriptional activation of the oncogenes c-SRC and c-Myc [4], [5], suggesting that hnRNPK may cooperate with additional oncoproteins to overexpress genes that promote tumor growth. PCBP1 is downregulated in metastatic cervical cancer cells [6] and metastatic breast cancer cells [7]. Knockdown of PCBP1 in the prostate cancer cell line LNCaP promotes androgen receptor (AR) protein targeting to the 3′ untranslated region of AR transcripts [8]. The recent finding that transforming growth factor-β-mediated phosphorylation of PCBP1 induced epithelial–mesenchymal transdifferentiation (EMT) [9], and the evidence that PCBP1 can down-regulate metastasis-associated PRL-3 phosphatase translation [10], indicate that PCBP1 could be a tumor suppressor. It has been suggested that PCBP2 also plays an important role in cancers such as leukemogenesis [11] and oral cancer [12]. Recently, two related reports demonstrated that PCBP2 is overexpressed in human glioma and facilitates glioma growth by targeting four-and-a-half LIM domain 3 (FHL3), which was recently shown to act as tumor suppressor [13], [14]. PCBP2 overexpression is due to the down-regulation of SIRT6, which targets to the promoter of PCBP2 and deacetylates H3K9ac [14].
However, the role of PCBPs in other cancer types, gastric carcinoma for example, remains unknown. Recently, Ghanem et al. [15] showed a specific enrichment of the RNA-binding proteins PCBP1 and PCBP2 in chief cells of the murine gastric mucosa. PCBP1/2 expression correlates with gastric gland elongation in the post-natal period. This finding indicates that PCBPs may act in gastric development and diseases. Here in this study, we show that PCBP2 is overexpressed in human gastric carcinoma and predicts poor survival. We provide evidence that PCBP2 facilitates gastric cancer growth and inhibits apoptosis by targeting miR-34a.
Section snippets
Patients
One hundred and fifty-four cases of gastric cancer with full case history and paraffin-embedded tissue between January 1997 and December 2006 were collected at Huashan Hospital, Fudan University (Shanghai). The patients included 87 (56.5%) males and 67 (43.5%) females with a mean age of 59 years. Tumors were histologically classified into 73 (47.7%) intestinal gastric cancer and 81 (52.3%) diffuse gastric cancer. The diagnosis of gastric cancer was established using World Health Organization
PCBP2 overexpresses in human gastric cancer
To study the potential participation of the PCBP family in human gastric cancer, we firstly evaluated the mRNA levels of the members of PCBP family in human normal gastric mucosa (NGM) and gastric carcinoma tissues. The results showed that the PCBP2 was significantly increased in gastric carcinoma tissues compared to NGM, whereas the mRNA levels of other members did not change (Fig. 1A). To investigate whether this significance change in PCBP2 expression also exists in a larger cohort, we
Discussion
In the present study, we evaluated the changes in expression of PBCPs in human gastric carcinoma compared to normal gastric mucosa, and found that PCBP2 was overexpressed in human gastric carcinoma. The high expression of PCBP2 predicted poor overall and disease-free survival. We further demonstrated that PCBP2 facilitated gastric cancer cell growth and transformation using in vitro and in vivo evidence. Mechanically, we showed that PCBP2 maintained the survival of gastric cancer cells and
Conflict of interest
None.
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Advances in poly(rC)-binding protein 2: Structure, molecular function, and roles in cancer
2021, Biomedicine and PharmacotherapyCitation Excerpt :Furthermore, gain‐ and loss‐of‐function studies revealed that PCBP2 functions as a competing endogenous RNA for miR-34a to promote gastric carcinoma cell proliferation and colony formation in vitro (Fig. 3). Subcutaneous xenograft results also showed that PCBP2 facilitates gastric carcinoma cell growth in vivo [68]. In another recent study, PCBP2 was found to act as an oncogene by directly binding to cyclin-dependent kinase 2; this was assessed using a ribonucleoprotein immunoprecipitation assay and a biotin pulldown assay [69].
MiR-34a suppresses the proliferation and invasion of gastric cancer by modulating PDL1 in the immune microenvironment
2020, Molecular and Cellular ProbesCitation Excerpt :Particularly, several studies have suggested that miR-34a mediates the suppression of gastric tumors by regulating the expression of downstream genes, such as PDGFR [13], Survivin [39], IGF2BP3 [40], MET [13,41], TGIF2 [42], and HK1 [43]. Similarly, the upstream genes such as SIRT7 [44] and PCBP2 [45] have also been identified to be regulated by miR-34a in gastric cancer. Based on our results, PDL1 is a novel downstream gene of miR-34a in gastric cancer, which holds immense importance in the understanding of the functional mechanism networks of miR-34a in gastric cancer.
Cancer the‘RBP'eutics–RNA-binding proteins as therapeutic targets for cancer
2019, Pharmacology and TherapeuticsCitation Excerpt :Nevertheless, more studies are needed to further elucidate the role of PCBP4 in tumor suppression. PCBP2 was found to be up-regulated in several types of cancers, such as gastric cancer, esophageal cancer, glioblastoma, and HCC (Hu, Liu, Zhang, & Huang, 2014; Luo & Zhuang, 2017; J Ye et al., 2016; X Zhang et al., 2016). Consistent with this, knockdown of PCBP2 inhibited glioma cell growth both in vitro and in nude mice (W. Han et al., 2013).
Poly (C)-binding protein 2 (PCBP2) promotes the progression of esophageal squamous cell carcinoma (ESCC) through regulating cellular proliferation and apoptosis
2016, Pathology Research and PracticeCitation Excerpt :For example, in human oral cancer cells, the overexpression of PCBP2 induced apoptosis [19]. However, other research found that PCBP2 could facilitate cancer growth and inhibit apoptosis in gastric cancer [11]. These facts demonstrated that PCBP2 might be considered as a significant target for diagnosis and treatment in different tumors.
β2-adrenergic receptor signaling promotes pancreatic ductal adenocarcinoma (PDAC) progression through facilitating PCBP2-dependent c-myc expression
2016, Cancer LettersCitation Excerpt :This finding implicated that PCBP2 might serve as a novel signaling transmitter of β2-AR in the promotion of PDAC development. PCBP2 has been reported to be involved in multiple types of tumors, such as glioma, gastric carcinoma and oral cancer [20–22]. In glioma, significantly elevated expression of PCBP2 was observed in the tumor tissues and cell lines.