Elsevier

Biomedicine & Pharmacotherapy

Volume 83, October 2016, Pages 1220-1226
Biomedicine & Pharmacotherapy

Original article
Long non-coding RNA UCA1 promotes the tumorigenesis in pancreatic cancer

https://doi.org/10.1016/j.biopha.2016.08.041Get rights and content

Abstract

The contribution of long non-coding RNAs (lncRNAs) to tumorigenesis and metastasis of pancreatic cancer (PC) remains largely unknown. Urothelial cancer-associated 1 (UCA1), which is an originally identified lncRNA in bladder cancer, has be proved to play a pivotal role in bladder cancer progression and embryonic development. In this study, we detected the mRNA expression of UCA1 in 128 PC patients by qRT-PCR, and found that UCA1 expression was significantly, up-regulated in tumor tissues than that in matched adjacent non-tumor tissues (p < 0.05). Clinicopathological analysis demonstrated that UCA1 expression in PC significantly correlated with malignant potential factors such as tumor size (p = 0.021), depth of invasion (p = 0.033), CA19-9 level (p = 0.034) and tumor stage (p = 0.013). Cox proportional hazards regression analysis also confirmed that high UCA1 expression was an independent prognostic biomarker of PC (p = 0.046), which led to an obviously shorter 5-year overall survival (OS) compared to those patients with low UCA1 expressions (p = 0.018). Furthermore, we effectively down-regulated UCA1 mRNA expression by transfecting RNA interfere fragments into SW-1990 cells, and our results in vitro indicated that down-regulation of UCA1 could effectively inhibit the cell proliferative activities, induce apoptotic rate and cause cell cycle arrest in PC cells (p < 0.05). Meanwhile, UCA1 expression negative-correlated with p27 in PC tissues (r2 = 0.46, p < 0.01), and knockdown of p27 partly abrogated the cell proliferative activities caused by UCA1 (p < 0.05). Our results raised the possibility of using UCA1 as a potential prognostic biomarker and therapy target of PC, and down-regulation of UCA1 might be considered to be a novel molecular treatment strategy for patients with PC.

Introduction

Pancreatic cancer (PC), a common digestive tumor, is the sixth leading cause of cancer-related deaths in the world [1]. Despite the surgical techniques for treatment including surgery, chemotherapy and radiotherapy, the 5-year overall survival rate is still less than 5% [2], [3]. It is characterized by a high tendency for aggressive invasion and distant metastasis, resulting in a high mortality rate. Because of the lack of early symptoms and early detection, PC patients are usually diagnosed at an advanced stage [4]. Thus it is an urgent need to identify new potential biomarkers which can identify biological characteristics of tumors, and predict prognosis and response to therapy.

Long non-coding RNAs (lncRNAs) are a class of transcripts longer than 200 nucleotides, which are typically transcribed by RNA polymerase II [5], [6], [7]. Accumulating evidence have showed that lncRNAs participate in the regulation of various biological processes, such as cell proliferation, differentiation and chromosome inactivation [8], [9]. Moreover, several studies have demonstrated that down-regulated of lncRNAs or aberrant lncRNAs expression can be potentially used as biomarkers for PC [10], [11].

Urothelial cancer-associated 1 (UCA1) is an originally identified non-coding RNA, whose expression correlated with the tumorigenesis of bladder cancer [12]. Subsequently, several studies demonstrated that UCA1 could serve as tumor-promoters in bladder cancer, urothelial carcinoma, breast cancer, colorectal cancer and gastric cancer [13], [14], [15], [16]. For example, Huang et al. found that UCA1 could suppress the tumor suppressor p27 through combining hnRNP I and promoting breast cancer cell growth in vitro and vivo [14]. Li et al. confirmed that UCA1 expression was an independent marker for predicting the prognosis of esophageal squamous cell carcinoma [17]. However, the expression of UCA1 in PC, and a link between UCA1 and tumor clinicopathological characteristics have not been reported until now.

In the present study, we detected the expression of UCA1 in PC tissues and cell lines. Clinicopathological and prognostic values of UCA1 in PC patients were also investigated. Furthermore, we also explored whether abnormal expression of UCA1 regulated cell proliferation, apoptosis and cell cycle in PC cells.

Section snippets

Patients and specimens

A total of 128 PC samples and matched adjacent non-tumor tissues were obtained at the Department of General Surgery, Ningbo No. 2 Hospital from 2006 to 2009. Each patient was histopathologically diagnosed as PC. All patients received operation as initial systemic treatment. The inclusion criteria were as follows: 1) patients with PC confirmed by histopathology with radical operation; 2) patients received operation as initial systemic treatment. Patients who had received preoperative neoadjuvant

UCA1expressions in PC specimens and cell lines

In a preliminary experiment, we assessed the levels of UCA1 in 128 PC tissues and their matched adjacent non-tumor tissues. Our data implied that the relative expression of UCA1 in cancer tissues of PC patients (median expression level: 2.74, range 1.91–3.58) was significantly higher than that in matched NATs (median expression level: 1.55, range1.22–1.87) (p < 0.05, Fig. 1a). Besides, we examined the expression of UCA1 in 4 PC cell lines (Panc-1, Bxpc-3, Capan-1, SW-1990) and the normal

Discussion

It is well known that protein-coding genes account for only 2% of the human genome, whereas over 90% of human genome transcriptional products are non-coding RNAs [20], [21]. To date, accumulating studies have reported that lncRNAs have been involved in several cell behaviors, such as embryonic development, differentiation, apoptosis and motility [22], [23], [24]. Meanwhile, Dys-regulations of lncRNAs have been shown to associate with the modulation of proliferation and invasion of tumors [25].

Conflict of interest

The authors declare that they have no conflicts of interest concerning this article.

Acknowledgements

This study was supported by grants from the National youthful Science Foundation of China (No. 81302147) and the Subject Project of the Construction of the Regional Special Disease Center of Zhejiang Province (No. 2014-98).

References (33)

  • X. Guo et al.

    Long non-coding RNAs function annotation: a global prediction method based on bi-colored networks

    Nucleic Acids Res.

    (2013)
  • C. Arriaga-Canon et al.

    A long non-coding RNA promotes full activation of adult gene expression in the chicken alpha-globin domain

    Epigenetics

    (2014)
  • S. Peter et al.

    Identification of differentially expressed long noncoding RNAs in bladder cancer

    Clin. Cancer Res.

    (2014)
  • E.J. Pang et al.

    Overexpression of long non-coding RNA MALAT1 is correlated with clinical progression and unfavorable prognosis in pancreatic cancer

    Tumour Biol.

    (2015)
  • Y.W. Sun et al.

    A novel long non-coding RNA ENST00000480739 suppresses tumour cell invasion by regulating OS-9 and HIF-1alpha in pancreatic ductal adenocarcinoma

    Br. J. Cancer

    (2014)
  • Y. Wang et al.

    Long non-coding RNA UCA1a(CUDR) promotes proliferation and tumorigenesis of bladder cancer

    Int. J. Oncol.

    (2012)
  • Cited by (68)

    • Biogenesis, classification, and role of LncRNAs in tumor angiogenesis: A focus on tumor and its neighbouring cells, and interaction with miRNAs

      2022, Process Biochemistry
      Citation Excerpt :

      Evidence suggests that inhibiting bladder cancer growth by silencing the lncRNA UCA1 using CRISPR/Cas9 is feasible [61]. Notably, lncRNA UCA1 is also abundantly expressed in PC, and its downregulation has been shown to effectively inhibit PC cell growth, increase apoptosis, and cause cell cycle arrest [7]. Based on these hints, we considered the feasibility of using CRISPR/Cas9 to suppress UCA1 expression as a tumor therapy.

    • Emerging roles of long noncoding RNAs in chemoresistance of pancreatic cancer

      2022, Seminars in Cancer Biology
      Citation Excerpt :

      LncRNA urothelial carcinoma-associated 1 (UCA1) is a 1.4 kb long transcript that is located on 19p13.12 positive strand, which was originally recognized in human bladder cancer cell line [137]. LncRNA UCA1 was reported to promote proliferation, inhibit apoptotic rate and cell cycle arrest in pancreatic cancer [138]. LncRNA UCA1 targets miR-107 and subsequently promotes ITGA2 expression and increases migration and invasion of pancreatic cancer cells [139].

    View all citing articles on Scopus
    View full text