Biomedical Research

Abstract

Metastasis is one of the major obstacles limiting the success treatment of cancer. Annexin A1 (ANXA1)
is a key member of the subfamily and belongs to the multi-gene family of annexins, which is known to
play an important role in cancer progression and metastasis. Although there were controversies
surrounding the relationship between ANXA1 and metastasis, the role of ANXA1 in cancer metastasis
has been increasingly recognized. Numerous ANXA1-related signaling pathways are involved in cancer
metastasis. Recently through microarray experiments demonstrate that ANXA1 could regulate
microRNAs (miRNAs) in cancer, such as miRNA-196a (miR-196a), microRNA-26 (miR-26) and
microRNA-562 (miR-562), which promoted cell proliferation and angiogenesis. ANXA1 could regulate
miRNAs to directly target NF-κB, estrogen receptor (ER) and angiogenesis gene transcripts. Thus,
ANXA1 mediates cancer metastasis may via regulation of miRNA signaling. This review describes the
mechanism by which ANXA1 contributes to cancer metastasis and summarizes new advances in
research in ANXA1associated cancer metastasis.

Keywords

Carcinoma, ANXA1, Cancer, Metastasis, miRNA

Abbreviations

ANXA1: Annexin A1; miRNAs: microRNAs; ER: Estrogen Receptor; EGFR: Epidermal Growth Factor Receptor; FPR: Formyl Peptide Receptors; BC: Breast Cancer; miR-196a: miRNA-196a; miR-26: microRNA-26; miR-562: microRNA-562; GC: Gastric Cancer; LC: Lung Cancer; NSCLC: Non-Small Cell Lung Cancer; PC: Prostate Cancer.

Introduction

Metastasis is the most common causes of death in cancer patients. In particular cancer cell migration and invasion play a crucial role in the progression and metastasis of cancer [1,2]. Thus, a better understanding of the mechanisms underlying these processes is important for the development of novel anticancer agents in order to improve clinical outcome.

ANXA1 is a key member of the subfamily and belongs to the multi-gene family of annexins. ANXA1 protein binds the cellular membrane phospholipids in a Ca²⁺ regulated manner, such as Epidermal Growth Factor Receptor (EGFR), Estrogen Receptor (ER), and Formyl Peptide Receptors (FPR). ANXA1 has been found in several tissues and regulates physiological mechanisms such as cell migration, anti-inflammatory effects, membrane transport, apoptosis and differentiation [7-11].

MiRNAs are a group of non-coding RNAs which have been shown to regulate many genes [12]. Recently through microarray experiments demonstrate that ANXA1 could regulate microRNAs (miRNAs) in cancer, such as miRNA-196a (miR-196a), microRNA-26 (miR-26) and microRNA-562 (miR-562), which promoted cell proliferation and angiogenesis [13]. ANXA1 could regulate miRNAs to directly target NF-κB, ER and angiogenesis [14]. This binding interaction results in either mRNA degradation of the gene transcripts or inhibition of translation [14]. Thus, ANXA1 mediates cancer metastasis may via regulation of miRNA signaling.

ANXA1 and Breast Cancer

Breast Cancer (BC) develops through sequential stages from normal ductal epithelium to hyperplasia, ductal carcinoma in situ, invasive cancer, and metastatic carcinoma [15]. In order to improve BC diagnosis and treatment, it is necessary to have a better understanding of etiology. ANXA1 regulates in the mammary gland during the developmental and takes part in intracellular signaling. Several papers indicated that ANXA1 was related to unfavorable prognostic factors in patients with BC [16]. Loss of ANXA1 expression both in DCIS and invasive carcinoma compared to normal epithelium and benign breast diseases in previous studies [16]. Some studies have shown that a higher level of ANXA1 in lymph node metastasis in comparison with primary BC [17,18]. A similar finding was observed in human breast cancer by a tissue microarray analysis [19].

ANXA1 could regulate miRNAs in breast cancer and it is a target of miRNA-196a (miR-196a), microRNA-26 (miR-26) and microRNA-562 (miR-562) promoted cell proliferation and angiogenesis [13,20,21]. In vivo experiments demonstrate that expression of miR-196a in breast cancer cell induced significantly promotes cell growth [22]. ANXA1 can inhibit the expression of miR-196a, which could stimulation of c-myc and NF-κB expression, regulates BC cell proliferation. ANXA1 could regulate miR-26 and miR-562 directly targeted the NF-κB pathway by targeting the 3’UTR and inhibiting expression of p65 and NF-κB respectively. Overexpression of miR-562 and miR-26 could enhance endothelial tube formation in BC cells.

ANXA1 and Gastric Cancer

Gastric Cancer (GC) remains one of the most common cancers worldwide, and more than one third of GC cases occur in China [23]. However, there are few therapeutic options available for gastric cancer and identification of new biologic targets in patients with GC may contribute to improvement in their outcome.

There has been evidence that inflammation is implicated in GC development [24]. ANXA1 is an endogenous anti-inflammatory protein with a number of biological functions, such as cell migration, inflammation and apoptosis. ANXA1 maybe a poor prognostic factors in patients with GC. Cheng et al. analyze 118 GC patients by immunohistochemical staining [25]. The results show that high ANXA1 expression was associated with more serosal invasion, more peritoneal metastasis, and poorer overall survival in GC patients. A similar finding was observed in gastrointestinal cancer [26].

Accumulated evidences have indicated that ANXA1 sub-cellular localization are involved in the development, invasion, metastasis and drug resistance of a variety of cancers. There was a study suggestion ANXA1 cytoplasm staining correlation with esophageal and esophagogastric junction adenocarcinoma patient’s survival and loss of ANXA1 expression correlated with gastric cancer patient’s poor outcome [27,28]. Recently study evaluating the prognostic significance of nuclear staining of ANXA1 in oral squamous cell carcinoma patients showed a lower overall survival, whereas decrease of ANXA1 membranous staining in carcinoma do not be involved in oral carcinogenesis [29]. In addition, it has been suggested that ANXA1 nuclear translocation participates in the regulation of cellular proliferation [30,31]. Therefore, it’s suggested that the different subcellular distribution of ANXA1 may also contribute to tumorigenesis and progression in gastric cancer.

In our previous study, we analyzed the correlation of both cytoplasmic and nuclear expression of ANXA1 with different clinicopathological parameters in GC. Nuclear ANXA1 expression was associated significantly with Tumor-Node-Metastasis (pTNM) stage, the nuclear staining of ANXA1 is associated with poor prognosis. And cytoplasmic ANXA1 expression did not correlate with any of pathologic parameters.Our study suggests nuclear localization of ANXA1 correlates with advanced disease stage and peritoneal dissemination in gastric cancer [32]. However, we cannot find any studies about ANXA1 regulate miRNA in GC.

ANXA1 and Other Cancers

Lung Cancer (LC) is the leading cause of cancer‑associated mortality worldwide [33]. A previous study demonstrated that ANXA1 expression was significantly higher in patients with Non-Small Cell Lung Cancer (NSCLC), as compared with in control subjects, the similar finding was observed in lung squamous carcinoma cell [34,35]. However, the possible biological function of ANXA1 in NSCLC remains to be eluci­dated

ANXA1 is also expression in prostate cancer, and this protein is mainly described to be reduced [36]. In normal prostate tissue ANXA1 expression seems to be confined in basal cells and these latter are extremely rare in Prostate Cancer (PC) mass. The high expression of ANXA1 is maintenance of stem-like in PC cells, which could regulate metastasis by favoring cell migration intracellularly [37].

In esophageal cancer, breast cancer and endometrial cancer, Luthra et al. demonstrated an inverse correlation between ANXA1 mRNA levels and miR-196a in 12 different esophageal, breast and endometrial cancer cell lines and ANXA1 expression could regulation of miR-196a as a marker of esophageal cancer [21].

Conclusion

The past several years have seen significant strides in elucidating the role of ANXA1 in cancer metastasis. Data are starting to accumulate defining ANXA1 mediates cancer metastasis may via regulation of miRNA signaling.

Given this, in the foreseeable future, drug treat­ment may be guided by individualized genotype databases that can enable customized drug dos­ing to enhance therapeu­tic effect. The past several years have provided mounting evidence for expression of ANXA1 in can­cer and ANXA1 expression frequently correlates with cancer metastasis.

Ethics Approval and Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Author’s Contributions

Chaoyang Xu-explored the topic, defined the formation and drafted the manuscript, Liming Huang and Songxiang Wangrevised the manuscript and helped its drafting. Zhinong Jiang read and approved the final manuscript.

Acknowledgment

We are grateful to the anonymous reviewers whose suggestions and comments contributed to the significant improvement of this paper.

Funding

This study was supported by grants from the National Natural Science Foundation of China (Grant no: 81341135), Zhejiang non-profit technology applied research projects of China (Grant no: LGF20H160017), Shaoxing non-profit technology applied research projects of China (Grant no: 2017B70037 2017QN002).

Competing Interests

The authors declare that they have no competing interests.

Availability of Data and Materials

Please contact author for data requests.

Consent for Publication

Not applicable.

References

1. Chakravarthi BV, Nepal S, Varambally S. Genomic and epigenomic alterations in cancer. Am J Pathol 2016; 186: 1724-1735.
2. Locke WJ, Clark SJ. Epigenome remodelling in breast cancer: insights from an early in vitro model of carcinogenesis. Breast Cancer Res 2012; 14: 215.
3. Grewal T, Enrich C. Annexins-modulators of EGF receptor signalling and trafficking. Cell Signal 2009; 21: 847-858.
4. Ang EZ, Nguyen HT, Sim HL, Putti TC, Lim LH. Annexin-1 regulates growth arrest induced by high levels of estrogen in MCF-7 breast cancer cells. Mol Cancer Res 2009; 7: 266-274.
5. Khau T, Langenbach SY, Schuliga M, Harris T, Johnstone CN, Anderson RL, Stewart AG. Annexin-1 signals mitogen-stimulated breast tumor cell proliferation by activation of the formyl peptide receptors (FPRs) 1 and 2. FASEB J 2011; 25: 483-496.
6. Belvedere R, Bizzarro V, Forte G, Dal Piaz F, Parente L, Petrella A. Annexin A1 contributes to pancreatic cancer cell phenotype, behaviour and metastatic potential independently of Formyl Peptide Receptor pathway. Sci Rep 2016; 6: 29660.
7. Bizzarro V, Belvedere R, Milone MR, Pucci B, Lombardi R, Bruzzese F, Popolo A, Parente L, Budillon A, Petrella A. Annexin A1 is involved in the acquisition and maintenance of a stem cell-like/aggressive phenotype in prostate cancer cells with acquired resistance to zoledronic acid. Oncotarget 2015; 6: 25076-25092.
8. Pan B, Kong J, Jin J, Kong J, He Y, Dong S, Ji L, Liu D, He D, Kong L, Jin DK, Willard B, Pennathur S, Zheng L. A novel anti-inflammatory mechanism of high density lipoprotein through up-regulating annexin A1 in vascular endothelial cells. Biochim Biophys Acta 2016; 1861: 501-512.
9. Solito E, Christian HC, Festa M, Mulla A, Tierney T, Flower RJ, Buckingham JC. Post-translational modification plays an essential role in the translocation of annexin A1 from the cytoplasm to the cell surface. FASEB J 2006; 20: 1498-1500.
10. Arora S, Lim W, Bist P, Perumalsamy R, Lukman HM, Li F, Welker LB, Yan B, Sethi G, Tambyah PA, Fairhurst AM, Alonso S, Lim LH. Influenza A virus enhances its propagation through the modulation of Annexin-A1 dependent endosomal trafficking and apoptosis. Cell Death Differ 2016; 23: 1243-1256.
11. Bizzarro V, Fontanella B, Franceschelli S, Pirozzi M, Christian H, Parente L, Petrella A. Role of Annexin A1 in mouse myoblast cell differentiation. J Cell Physiol 2010; 224: 757-765.
12. Xie X, Lu J, Kulbokas EJ, Golub TR, Mootha V, Lindblad-Toh K, Lander ES, Kellis M. Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals. Nature 2005; 434: 338-345.
13. Anbalagan D, Yap G, Yuan Y, Pandey VK, Lau WH, Arora S, Bist P, Wong JS, Sethi G, Nissom PM, Lobie PE, Lim LH. Annexin-A1 regulates microRNA-26b* and microRNA-562 to directly target NF-κB and angiogenesis in breast cancer cells. PLoS One 2014; 9: e114507.
14. Pin AL, Houle F, Fournier P, Guillonneau M, Paquet ÉR, Simard MJ, Royal I, Huot J. Annexin-1-mediated endothelial cell migration and angiogenesis are regulated by vascular endothelial growth factor (VEGF)-induced inhibition of miR-196a expression. J Biol Chem 2012; 287: 30541-30551.
15. Dyrstad SW, Yan Y, Fowler AM, Colditz GA. Breast cancer risk associated with benign breast disease: systematic review and meta-analysis. Breast Cancer Res Treat 2015; 149: 569-575.
16. Yom CK, Han W, Kim SW, Kim HS, Shin HC, Chang JN, Koo M, Noh DY, Moon BI. Clinical significance of annexin A1 expression in breast cancer. J Breast Cancer 2011; 14: 262-268.
17. Alldridge LC, Harris HJ, Plevin R, Hannon R, Bryant CE. The annexin protein lipocortin 1 regulates the MAPK/ERK pathway. J Biol Chem 1999; 274: 37620-37628.
18. Wang LP, Bi J, Yao C, Xu XD, Li XX, Wang SM, Li ZL, Zhang DY, Wang M, Chang GQ. Annexin A1 expression and its prognostic significance in human breast cancer. Neoplasma 2010; 57: 253-259.
19. Shen D1, Nooraie F, Elshimali Y, Lonsberry V, He J, Bose S, Chia D, Seligson D, Chang HR, Goodglick L. Decreased expression of annexin A1 is correlated with breast cancer development and progression as determined by a tissue microarray analysis. Hum Pathol 2006; 37: 1583-1591.
20. Nagpal N, Ahmad HM, Molparia B, Kulshreshtha R. MicroRNA-191, an estrogen-responsive microRNA, functions as an oncogenic regulator in human breast cancer. Carcinogenesis 2013; 34:1889-1899.
21. Luthra R, Singh RR, Luthra MG, et al. MicroRNA-196a targets annexin A1: a microRNA-mediated mechanism of annexin A1 downregulation in cancers. Oncogene 2008; 27: 6667-6678.
22. Yuan Y, Anbalagan D, Lee LH. ANXA1 inhibits miRNA-196a in a negative feedback loop through NF-kB and C-Myc to reduce breast cancer proliferation. Oncotarget 2016; 7: 27007-27020.
23. Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H. Gastric cancer. Lancet 2016: 30354-30353.
24. Raei N, Behrouz B, Zahri S, Latifi-Navid S. Helicobacter pylori Infection and dietary factors act synergistically to promote gastric cancer. Asian Pac J Cancer Prev 2016; 17: 917-921.
25. Cheng TY, Wu MS, Lin JT, Lin MT, Shun CT, Huang HY, Hua KT, Kuo ML. Annexin A1 is associated with gastric cancer survival and promotes gastric cancer cell invasiveness through the formyl peptide receptor/extracellular signal-regulated kinase/integrin beta-1-binding protein 1 pathway. Cancer 2012; 118: 5757-5767.
26. Yu G, Wang J, Chen Y, Wang X, Pan J, Li Q, Xie K. Tissue microarray analysis reveals strong clinical evidence for a close association between loss of annexin A1 expression and nodal metastasis in gastric cancer. Clin Exp Metastasis 2008; 25: 695-702.
27. Wang KL, Wu TT, Resetkova E, Wang H, Correa AM, Hofstetter WL, Swisher SG, Ajani JA, Rashid A, Hamilton SR, Albarracin CT. Expression of annexin A1 in esophageal and esophagogastric junction adenocarcinomas: association with poor outcome. Clin Cancer Res 2006; 12: 4598-4604.
28. Sato Y, Kumamoto K, Saito K, Okayama H, Hayase S, Kofunato Y, Miyamoto K, Nakamura I, Ohki S, Koyama Y, Takenoshita S. Up-regulated Annexin A1 expression in gastrointestinal cancer is associated with cancer invasion and lymph node metastasis. Exp Ther Med 2011; 2: 239-243.
29. Lin CY, Jeng YM, Chou HY, Hsu HC, Yuan RH, Chiang CP, Kuo MY. Nuclear localization of annexin A1 is a prognostic factor in oral squamous cell carcinoma. J Surg Oncol 2008; 97: 544-550.
30. Alldridge LC, Bryant CE. Annexin 1 regulates cell proliferation by disruption of cell morphology and inhibition of cyclin D1 expression through sustained activation of the ERK1/2 MAPK signal. Exp Cell Res 2003; 290: 93-107.
31. Alves VA, Nonogaki S, Cury PM, Wu¨nsch-Filho V, de Carvalho MB, Michaluart-Ju′nior P, Moyses RA, Curioni OA, Figueiredo DL, Scapulatempo-Neto C, Parra ER, Polachini GM, Silistino-Souza R, Oliani SM, Silva-Júnior WA, Nobrega FG. Head and neck genome project/GENCAPO. Annexin A1 subcellular expression in laryngeal squamous cell carcinoma. Histopathology 2008; 53: 715-727.
32. Zhu F, Xu C, Jiang Z, Jin M, Wang L, Zeng S, Teng L, Cao J. Nuclear localization of annexin A1 correlates with advanced disease and peritoneal dissemination in patients with gastric carcinoma. Anat Rec (Hoboken) 2010; 293: 1310-1314.
33. Devarakonda S, Morgensztern D, Govindan R. Genomic alterations in lung adenocarcinoma. Lancet Oncol 2015; 16: 342-351.
34. Fang Y, Guan X, Cai T, Long J, Wang H, Xie X, Zhang Y. Knockdown of ANXA1 suppresses the biological behavior of human NSCLC cells in vitro. Mol Med Rep 2016; 13: 3858-3866.
35. Nan Y, Yang S, Tian Y, Zhang W, Zhou B, Bu L, Huo S. Analysis of the expression protein profiles of lung squamous carcinoma cell using shot-gun proteomics strategy. Med Oncol 2009; 26: 215-221.
36. Mu D, Gao Z, Guo H, Zhou G, Sun B. Sodium butyrate induces growth inhibition and apoptosis in human prostate cancer DU145 cells by up-regulation of the expression of annexin A1. PLoS One 2013; 8: e74922.
37. Bizzarro V, Belvedere R, Milone MR, Pucci B, Lombardi R, Bruzzese F, Popolo A, Parente L, Budillon A, Petrella A. Annexin A1 is involved in the acquisition and maintenance of a stem cell-like/aggressive phenotype in prostate cancer cells with acquired resistance to zoledronic acid. Oncotarget 2015; 6: 25076-25092.