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      High Expression of ANXA2 Pseudogene ANXA2P2 Promotes an Aggressive Phenotype in Hepatocellular Carcinoma

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          Abstract

          Objective

          Accumulating evidence suggests that pseudogenes play potential roles in the regulation of their cognate wild-type genes, oncogenes, and tumor suppressor genes. ANXA2P2 (annexin A2 pseudogene 2) is one of three pseudogenes of annexin A2 that have recently been shown to be aberrantly transcribed in hepatocellular carcinoma (HCC) cells. However, its clinical meaning and biological function in HCC have remained unclear. Therefore, the present study was aimed at exploring the prognostic value of a high expression of ANXA2P2 in HCC tissue and at identifying whether it can affect the efficacy of targeted drugs (sorafenib, regorafenib, and lenvatinib).

          Methods

          We obtained ANXA2P2 mRNA expression levels from The Cancer Genome Atlas (TCGA) RNA sequence database. The expression levels of ANXA2P2 in 49 pairs of intratumoral and peritumoral liver tissues were examined by RT-PCR. Wound healing and transwell assays were performed to confirm the tumor-promoting properties of ANXA2P2 in HCC cells. CCK8 assay was conducted to identify whether ANXA2P2 can affect the growth of HCC cells when administered with targeted drugs (sorafenib, regorafenib, and lenvatinib).

          Results

          The expression of ANXA2P2 in HCC tissues was significantly higher than that in adjacent cancerous tissues from TCGA database and validation group. Additionally, patients with high ANXA2P2 expression in HCC tissue had a shorter overall survival, whereas no statistically significant correlation was found between ANXA2P2 expression and disease-free survival ( p = 0.08) as well as other clinical parameters, such as age, gender, histological grade, T classification, stage, albumin level, alpha-fetoprotein, and vascular invasion ( p = 0.7323, 0.8807, 0.5762, 0.8515, 0.7113, 0.242, 1.0000, and 0.7685, respectively). Furthermore, in vitro experiments showed that knockdown of ANXA2P2 inhibited migration and invasion of HCC cells but did not have an influence on the HCC cell proliferation when treated with targeted drugs (sorafenib, regorafenib, and lenvatinib).

          Conclusion

          Our study confirmed elevated ANXA2P2 expression levels in HCC tissue compared with adjacent noncancerous tissue and a worse prognosis of patients with high ANXA2P2 levels in the HCC tissue. The newly found properties of promoting migration and invasion of ANXA2P2 in HCC help to explain this phenomenon. ANXA2P2 could be a novel and suitable predicative biomarker for the risk assessment of recurrence or metastasis of HCC patients but may not be effective to predict the efficacy of targeted drugs.

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          Most cited references31

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          Emerging trends in hepatocellular carcinoma incidence and mortality.

          Basile Njei, Yaron Rotman, Ivo Ditah … (2015)
          The rise in incidence of hepatocellular carcinoma (HCC) in the United States has been well documented. The purpose of this analysis was to examine temporal trends in HCC incidence, mortality, and survival within the U.S. population. The Surveillance, Epidemiology, and End Results data were used to examine incidence and incidence-based (IB) mortality in HCC from 1973 to 2011. Secular trends in age-adjusted incidence and IB mortality by sex and cancer stage were characterized using the Joinpoint Regression program. In 1973, HCC incidence was 1.51 cases per 100,000, whereas in 2011, HCC incidence was 6.20 cases per 100,000. Although HCC incidence continues to increase, a slowing of the rate of increase occurs around 2006. In a sensitivity analysis, there was no significant increase in incidence and IB mortality from 2009 to 2011. There was a significant increase in overall median survival from the 1970s to 2000s (2 vs. 8 months; P < 0.001). On multivariable Cox's regression analysis, age, sex, race, tumor grade, stage at diagnosis, lymph/vascular invasion, number of primary tumors, tumor size, and liver transplant were independently associated with mortality.
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            Expressed pseudogenes in the transcriptional landscape of human cancers.

            Shanker Kalyana-Sundaram, Chandan Kumar-Sinha, Sunita Shankar … (2012)
            Pseudogene transcripts can provide a novel tier of gene regulation through generation of endogenous siRNAs or miRNA-binding sites. Characterization of pseudogene expression, however, has remained confined to anecdotal observations due to analytical challenges posed by the extremely close sequence similarity with their counterpart coding genes. Here, we describe a systematic analysis of pseudogene "transcription" from an RNA-Seq resource of 293 samples, representing 13 cancer and normal tissue types, and observe a surprisingly prevalent, genome-wide expression of pseudogenes that could be categorized as ubiquitously expressed or lineage and/or cancer specific. Further, we explore disease subtype specificity and functions of selected expressed pseudogenes. Taken together, we provide evidence that transcribed pseudogenes are a significant contributor to the transcriptional landscape of cells and are positioned to play significant roles in cellular differentiation and cancer progression, especially in light of the recently described ceRNA networks. Our work provides a transcriptome resource that enables high-throughput analyses of pseudogene expression. Copyright © 2012 Elsevier Inc. All rights reserved.
            Article 0 comments Cited 133 times – based on 0 reviews     Review now
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              The OCT4 pseudogene POU5F1B is amplified and promotes an aggressive phenotype in gastric cancer.

              K Tanaka, I Okamoto, Y Yamada … (2015)
              POU5F1B (POU domain class 5 transcription factor 1B), a processed pseudogene that is highly homologous to OCT4, was recently shown to be transcribed in cancer cells, but its clinical relevance and biological function have remained unclear. We now show that POU5F1B, which is located adjacent to MYC on human chromosome 8q24, is frequently amplified in gastric cancer (GC) cell lines. POU5F1B, but not OCT4, was also found to be expressed at a high level in GC cell lines and clinical specimens. In addition, the DNA copy number and mRNA abundance for POU5F1B showed a positive correlation in both cancer cell lines and GC specimens. Overexpression of POU5F1B in GC cells promoted colony formation in vitro as well as both tumorigenicity and tumor growth in vivo, and these effects were enhanced in the additional presence of MYC overexpression. Furthermore, knockdown of POU5F1B expression with a short hairpin RNA confirmed a role for the endogenous pseudogene in the promotion of cancer cell growth in vitro and tumor growth in vivo. POU5F1B overexpression induced upregulation of various growth factors in GC cells as well as exhibited mitogenic, angiogenic and antiapoptotic effects in GC xenografts. Finally, amplification of POU5F1B was detected in 17 (12%) of 145 cases of GC and was a significant predictor of poor prognosis in patients with stage IV disease. In conclusion, we found that the POU5F1B pseudogene is amplified and expressed at a high level in, as well as confers an aggressive phenotype on, GC, and that POU5F1B amplification is associated with a poor prognosis in GC patients.
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                Author and article information

                Contributors
                Sheng-li Yang:
                ORCID: http://orcid.org/0000-0002-2068-7618
                Jian-li Hu:
                ORCID: http://orcid.org/0000-0002-9321-0837
                Journal
                Journal ID (nlm-ta): Dis Markers
                Journal ID (iso-abbrev): Dis. Markers
                Journal ID (publisher-id): DM
                Title: Disease Markers
                Publisher: Hindawi
                ISSN (Print): 0278-0240
                ISSN (Electronic): 1875-8630
                Publication date Collection: 2019
                Publication date (Electronic): 10 February 2019
                Volume: 2019
                Electronic Location Identifier: 9267046
                Affiliations
                1Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
                2Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430077, China
                3Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550001, China
                Author notes

                Academic Editor: Sheng Pan

                Author information
                http://orcid.org/0000-0002-2068-7618
                http://orcid.org/0000-0002-9321-0837
                Article
                DOI: 10.1155/2019/9267046
                PMC ID: 6387700
                PubMed ID: 30881525
                SO-VID: 862f6627-11a6-4a72-a164-2b215fdc23de
                Copyright © Copyright © 2019 Qiu-shuang Wang et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 6 September 2018
                Date revision received : 9 November 2018
                Date accepted : 19 November 2018
                Funding
                Funded by: Chen Xiao-ping Foundation for the Development of Science and Technology of Hubei Province
                Award ID: CXPJJH11800001-2018317
                Funded by: Henry CSCO-Cancer Research Fund
                Award ID: Y-HR2017-033
                Funded by: Hubei Provincial Science and Technology Department
                Award ID: 2018CFC846
                Categories
                Subject: Research Article

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