Open access peer-reviewed chapter

MicroRNA-335-5p and Gastrointestinal Tumors

Written By

Pablo M. Santoro, Alejandra Sandoval-Bórquez and Alejandro H. Corvalan

Submitted: 26 February 2019 Reviewed: 29 July 2019 Published: 07 October 2019

DOI: 10.5772/intechopen.88895

From the Edited Volume

Non-Coding RNAs

Edited by Lütfi Tutar, Sümer Aras and Esen Tutar

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Noncoding genomics, i.e., microRNAs and long coding RNAs (lncRNA), is an emerging topic in gastrointestinal tumors. In particular, the coordinate deregulation of miRNA-335-5p across these tumors and its potential clinical applications is an example of this scenario. This chapter discusses the pathogenetic role of miRNA-335-5p in esophageal, gastric, colon, liver, gallbladder, and pancreatic tumors. This pathogenetic role is examined in the context of the competing endogenous network, the language through lncRNA that reduce the quantity of miRNA available to target mRNA. The translational application of miRNA-335-5p, through the aberrant methylation of the promoter region of MEST—its host gene—as a potential biomarker for noninvasive detection of gastric cancer, is also discussed.


  • ncRNA
  • miRNA-335-5p
  • gastrointestinal tumors
  • gastric cancer
  • competing endogenous
  • DNA methylation
  • biomarkers

1. Introduction

Gastrointestinal tumors (i.e., esophagus, stomach, colon, liver, gallbladder, and pancreas) are among the most common cancers by incidence and mortality in males and females worldwide [1]. Furthermore, projections of global mortality and disease burden indicate that new cases and deaths from these tumors will increase by 2030 [2]. Given this scenario, understanding of the molecular basis of gastrointestinal tumors is essential to the development of novel strategies for diagnosis and disease treatment. Large genomic studies focusing on protein-coding regions have identified multiple of genes recurrently mutated in gastrointestinal and other human neoplasms [3]. However, molecular classifications based on coding genes do not fully capture the clinical heterogeneity found in gastrointestinal tumors [4]. This observation indicates that other segments of the genome might also contribute to the emerging complexities observed in the development and progression of gastrointestinal neoplasms. In this chapter, we describe recent advances in our understanding of noncoding genome in gastrointestinal cancer. In particular, we will focus on miRNA-335-5p, since not only has it been found to be critically involved in myriad tumors but it has also proved to be a potential biomarker for noninvasive diagnosis of cancer and for the treatment of preneoplastic conditions [5, 6].


2. Noncoding genomics

The traditional view of the unidirectional flow (i.e., DNA-RNA-protein) of genomic data has been reclassified as multidirectional, based on the fact that even though 80% of DNA is transcribed into RNA, only 2% ultimately represent the coding genes which are translated into protein [7]. Therefore, the majority of RNA is defined as noncoding RNA (ncRNA) which in turn includes a wide range of RNA families such as those involved in the translation and splicing of messenger RNA (mRNA) as well as those associated with the modification of ribosomal RNA [7]. ncRNA also plays an essential role in all multiple biological functions, i.e., cell proliferation, apoptosis, cell migration and invasion, and cell differentiation being involved in each of the cancer hallmarks as well [8]. Based on the size of its sequence, ncRNA can be divided into short (~20–200 nucleotides; nt) and long ncRNA (200 to ~100,000 nt) [9].

2.1 Short noncoding RNAs

Short ncRNAs (sncRNAs) are represented by P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs), small interfering RNAs (siRNAs), and microRNAs (miRNAs). piRNAs (24–32 nt) are specialized for repression of mobile and other genetic elements in germ line cells (e.g., LINE1 piRNAs and piR-823) [10]. piRNAs and PIWI have been found deregulated in a tissue-specific manner in a variety of neoplasms, opening novel opportunities to diagnosis and treatment of disease [10]. siRNAs regulate posttranscriptional gene silencing and the defense against pathogen nucleic acids (e.g., L1-specific siRNA and oocyte endo-siRNAs) [11]. Therefore, they seem to have great potential in disease treatment, especially as promising epigenetic therapy through the silencing of cancer-related genes [12].

miRNAs represent the largest group of short noncoding RNAs, highly conserved and involved in the posttranscriptional regulation of gene expression in multicellular organisms [13]. miRNAs were discovered in the 1990s while studying fetal development of Caenorhabditis elegans [14]. To date, more than 30,000 miRNAs have been found in over 200 species [15]. In humans, the latest miRNA database miRBase release (Release 22.1) contains 2588 annotated mature miRNAs [15]. It is estimated that 60% of coding genes may be regulated by miRNAs. miRNAs have been found deregulated in a tissue-specific manner in human neoplasms, offering novel opportunities for diagnostic assessment and disease treatment [16].

Functional studies have confirmed critical roles of miRNAs in development and disease, particularly in cancer [17]. miRNAs can act as tumor suppressors or oncogenes, and miRNA mimics have shown promise in preclinical and early stages of clinical development [17]. miRNAs reflect the developmental lineage and differentiation state of the tumors being mostly downregulated compared with normal counterpart tissues [18]. Particularly, gastrointestinal tumors cluster together reflecting their common derivation from embryonic endoderm [18]. miRNA-335-5p is among the most frequently deregulated miRNAs in gastrointestinal tumors.

2.2 miRNA-335-5p structure and regulation of its expression

Although initially described in developmental biology, as differentially expressed and maternally imprinted during mouse and human lung development [19], later studies have shown that miRNA-335-5p is extensively deregulated in human tumors [20]. miRNA-335-5p is a transcript located on chromosome 7q32.2, in the second intron of the mesoderm-specific transcript homolog (MEST) gene [21], which encodes 17 different mRNAs [22]. In humans, the mature sequence of miRNA-335-5p forward strand, miRNA-335-5p, corresponds to 16 -UCAAGAGCAAUAACGAAAAAUGU-38 (, accession: MIMAT0000765, ID: hsa-miR-335-5p) [23]. The strong correlation between the expression of miRNA-335-5p and its host gene MEST suggests that the mechanism responsible for silencing miRNA-335-5p expression should be the promoter methylation of MEST [5, 24, 25] (Figure 1). The promoter of MEST gene contains three CpG islands upstream of transcriptional start site [26]. The treatment with 5-aza-2′-deoxycytidine (5-aza-dCyd) restores the expression levels of miRNA-335-5p in hepatocellular and gastric cancer [24, 27]. Furthermore, an inverse correlation between expression levels of miRNA-335-5p and its methylation status was revealed in these cancer tissues [24, 27].

Figure 1.

Linear regression model (blue line) using RNAseq data from 368 tumor samples from the stomach adenocarcinoma from The Cancer Genome Atlas (TCGA) consortium (taken from Sandoval-Bórquez et al. [5] with permission).

2.3 miRNA-335-5p and gastrointestinal malignancies

The coordinated deregulation of miRNA-335-5p across the gastrointestinal tract neoplasms implied the relevant role of this microRNA in these tumors. Esophageal adenocarcinoma (EAC) is one of the fastest rising incidences of cancers with a dismal prognosis [28]. EAC is the final stage of Barrett esophagus (BE), an adaptive response to chronic gastroesophageal reflux in which the squamous epithelium of the esophagus is replaced by glandular columnar epithelium [28]. By combining multidimensional genomic measurements from the TCGA, Xi and Zhang [29] proposed a genomic signature of five differentially expressed miRNAs including miRNA-335-5p that can be applied for novel diagnostic approaches and disease treatment. Gastric cancer (GC) remains the fifth cause in cancer incidence and the third cause of death by neoplasms worldwide [1]. GC is a highly heterogeneous disease with unique ethnogeographical associations [30, 31, 32]. Profiling studies have not identified miRNA-335-5p as part of any miRNA signatures with clinical significance. However, gene-specific approaches suggest that miRNA-335-5p is downregulated in GC and clinically associated with advanced TNM stage and worse prognosis [5, 33]. Functional studies have shown that exogenous expression of miRNA-335-5p deregulated many biological cell processes such as cell cycle, proliferation, apoptosis, migration, invasion, and metastasis [5, 25, 33, 34] (Figure 2). Of note, upregulation of miRNA-335-5p might be associated with tumor recurrence, the major factor of treatment failure in this disease [35].

Figure 2.

Cellular processes by which miRNA-335-5p contributes to their regulation though of different target genes in gastric cancer cell lines. miRNA-335-5p inhibits tumorigenicity, cell cycle, proliferation, apoptosis, migration, invasion, and metastasis [5, 25, 33, 34]. Abbreviations: CRKL, V-crk avian sarcoma virus CT10 oncogene homolog-like; CDH11, cadherin 11; PLAUR, plasminogen activator urokinase receptor; SP1, specificity protein 1; BCL-w, BCL2-like 2 (taken from Sandoval-Bórquez et al. [5] with permission).

Colorectal carcinoma (CRC) is the first cause of death by cancer in developed countries [1]. In this tumor downregulation of miRNA-335-5p has been associated with microsatellite instability (MSI) [36] and ability to discriminate between non-serrated and serrated adenomas [37]. Even though it has been described as upregulated in tumor samples relative to normal mucosa, functional studies have shown that its overexpression inhibits invasion and metastasis in CRC cell lines [3839]. The number of deaths for hepatocellular carcinoma (HCC) is nearly equal to the worldwide annual incidence of newly diagnosed cases [40]. Almost 80% of HCC is attributed to chronic hepatitides B and C which evolve to cirrhotic/fibrotic liver and ultimately HCC [41]. Screening of multiple miRNAs identified miRNA-335-5p among unique seven miRNA signatures that could be associated with the development HBV-related HCC [42]. Gallbladder carcinoma (GBC) is an infrequent but highly lethal biliary tract tumor mostly associated with the presence of gallstones and chronic inflammation [43]. Tumor suppressor and cancer-prone miRNAs have been identified in GBC including the downregulation of miRNA-335-5p, which together with other microRNAs produces a signature clinically associated with prognosis and prediction of treatment response [44]. Gene-specific analysis in paired tumor and normal tissues also confirms downregulation of miRNA-335-5p in association with histologic grade, stage, presence of metastases, and poor survival [45].

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, and because of the late presentation, as few as 20% of patients are candidates for curative treatment. Ectopic expression of miRNA-335-5p in pancreatic cancer cell lines significantly suppressed cell growth by inhibiting c-Met [46]. Other malignancies in which miRNA-335-5p is deregulated have been comprehensively described Luo et al. [20].

2.4 Long noncoding RNAs and the competing endogenous network of miRNA-335-5p in gastrointestinal malignancies

Long ncRNAs, which span from 200 to ~100,000 nt, make up the largest portion of the human noncoding transcriptome [47]. lncRNAs are essentially regulatory molecules implicated in multiple cellular processes in a tissue-specific manner [48]. Multiple reports have compiled the emerging role of the deregulated expression of lncRNAs in human tumors, and based on tissue-specific transcription, this novel class of genes holds strong potential as biomarkers and new therapeutic opportunities in cancer [49, 50, 51, 52]. lncRNAs reduce the quantity of miRNA available to target mRNA (i.e., “sponges”), through the miRNA response elements (MREs) contained within the lncRNA and the 3′UTR of mRNA, which serve as miRNA-binding sites [53]. Based on the relevance of these interactions, a new language has been proposed—the competing endogenous RNA (CERNA)- [52]. In the case of miRNA-335-5p, few CERNA networks have been described, which indicate that this is an emerging area of research in gastrointestinal tumors. As shown in Table 1, the lncRNA nuclear-enriched abundant transcript 1 (NEAT1) facilitates Sora resistance in HCC cells via negative regulation of miRNA-335/c-Met/Akt pathway that suppresses apoptosis [54]. The misato family member 2 (MSTO2P) has shown a high expression in parallel to a significantly low expression of miRNA-335-5p in clinical samples as well as in vitro [55]. As of this publication, no mRNA targets for this network have been described. Nuclear-enriched abundant transcript 1 (NEAT) is also upregulated in GC and promotes proliferation, migration, and invasion via targeting the miRNA-335-5p/ROCK1 axis [56]. The zinc finger E-box binding homeobox 1 antisense RNA 1 (ZEB1-AS1) has shown to be critical for the proliferation and invasion of GC cells by regulating miRNA-335-5p [57]. However, the mRNAs associated with this CERNA network are currently unknown.

lncRNA nameIDAbbreviationTarget coding geneTopicValidationReference
Nuclear-enriched abundant transcript 1ENSG00000245532NEAT1c-MetHepatocellular carcinomaIn vitro/in vivoChen and Xia [54]
Misato family member 2, pseudogeneENSG00000203761MSTO2PUnknownGastric cancer/metastasisClinical/in vitroLi et al. [55]
Nuclear-enriched abundant transcript 1ENSG00000245532NEAT1ROCK1Gastric cancerClinical/in vitroWang et al. [56]
ZEB1 antisense RNA 1ENSG00000237036ZEB1-AS1UnknownGastric cancerClinical/in vitro/in vivoZhang et al. [3, 57]

Table 1.

Competing endogenous RNA (CERNA) associated to miR-335-5p.

Further characterization of CERNA networks associated with the deregulation of miRNA-335-5p could be taken from the comprehensive evaluation of genes involved in metastasis and tumor invasion pathways after exogenous miRNA-335-5p expression [5]. Through this experiment up to 19 out of 62 (30.6%) genes were significantly increased [5]. Of note, miRNA-335-5p can target several messenger RNAs, and deregulation of miRNA-335-5p can effectively affect multiple signaling pathways leading to metastasis and tumor invasion [58]. In this scenario, ingenuity pathway analysis (IPA) narrowed the field to nine upregulated genes (CDH11, COL4A2, CTGF, CTSK, MMP7, PDGFA, PLAUR, TIMP1, and TIMP2) (Figure 3). Most of these upregulated genes belong to intracellular signaling pathways in cancer such as PI3K-Akt (COL4A2, MYC, PDGFA, SPP1), proteoglycans (HIF1A, MYC, PLAUR, TGFB1), and Hippo (CTGF, MYC, NF2, TGFB1). Among these genes, PLAUR significantly increased mRNA levels after knockdown of miRNA-335-5p expression in GC cells. PLAUR is a membrane-bound glycoprotein with a GPI anchor that encodes the receptor of urokinase-type plasminogen activator and binds and activates PLAU [59]. This activated serine protease converts plasminogen to plasmin, degrading all components of the extracellular matrix and promoting invasion and metastasis [60]. Furthermore, PLAUR has signaling properties through interactions with membrane-bound integrins, which are able to affect migration and cell proliferation [61]. In GC, the overexpression of PLAUR has been reported to be closely related to cell invasion and metastasis [62, 63]. In vitro analysis also showed a significant increase of PLAUR expression in miRNA-335-5p knockdown cells, and, consequently, cells overexpressing miRNA-335-5p exhibited a low level of PLAUR. Accordingly, elevated levels of PLAUR were observed in tumor tissues when compared with their paired non-tumor mucosa [5]. Another relevant gene overexpressed after exogenous miRNA-335-5p expression was CDH11, which encodes a type II classical cadherin, an integral membrane protein that mediates calcium-dependent cell-cell adhesion [64]. CDH11 has been reported as deregulated in various tumor types, suggesting a role in metastasis and tumor invasion [65, 66], and its overexpression was found in advanced cases of gastric cancer [67]. Binding experiments demonstrate the presence of direct targeting of miRNA-335-5p in the CDH11 gene [5]. Interestingly, preliminary data of potential targets of miRNA-335-5p in association with PLAUR and/or CDH11 reveal 15,898 new lncRNAs or 27,688 transcripts for further exploration of the role of CERNA in metastasis and tumor invasion pathways.

Figure 3.

Ingenuity pathway analysis (IPA) for network enrichment analysis identified metastasis and invasion downstream genes of miRNA-335. A network of nine significantly overexpressed (red) genes during miRNA-335 inhibition. The MAP tool shows activation and inhibition of neighboring genes and predicts activation of metastasis and invasion of cells in silico. *p < 0.05 (taken from Sandoval-Bórquez et al. [5] with permission).

2.5 Translational applications of miRNA-335-5p

Methylated cell-free DNA in plasma has emerged as a potential biomarker for diagnosis, prognosis, and prediction of treatment response in gastrointestinal tumors [24, 68]. In addition, several studies have shown that downregulation of miRNAs is associated with DNA methylation of the promoter region of its host genes [69].

Envisaging the clinical application of the downregulation of miRNA-335-5p in GC, Sandoval-Bórquez et al., [5] expand to plasma the reported inverse correlation between the expression of miRNA-335-5p and aberrant promoter methylation of its host gene (MEST) in tissues and cell lines [24] (Figure 4A). Furthermore, these authors demonstrated that this aberrant hypermethylation could be a surrogate biomarker for noninvasive diagnosis of GC since it was significantly found in GC cases in comparison with healthy donors (p = 0.029, Pearson’s correlation) (Figure 4B).

Figure 4.

Potential clinical application as noninvasive detection of GC by the downregulation of miRNA-335-5p. In (A) expression of miRNA-335-5p in plasma from GC patients and healthy donors by Cq of miRNA-335-5p, data were transformed to logarithmic values (−log), and results indicate the mean ± SD. In (B) methylation-specific PCR of the promoter region of MEST gene in plasma from GC patients and healthy donors, MyoD was used as a control of DNA conversion. MW, weight marker; M, PCR product with primers specific for methylated promoter region of MEST, host gene of miRNA-335-5p; PC, positive control of methylation (methylated GC cell line); NC, negative control of methylation (peripheral blood lymphocytes) (taken from Sandoval-Bórquez et al. [5] with permission).


3. Final conclusions

In this review, we summarize the role of miRNA-335-5p in gastrointestinal tumors with a focus on GC. We also explored the role of miRNA-335-5p in noncoding and coding gene networks and its downstream signaling pathways involved in the biological effects of tumor growth, invasion, and metastasis. This evidence supports the potential use of miRNA-335-5p in noninvasive diagnosis as well as therapeutic prospects in gastrointestinal cancers.



This research was funded by FONDECYT 1191928. We would like to thank Bree Johnson for English proofreading and editing the manuscript.


Conflict of interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.


  1. 1. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. International Journal of Cancer. 2019;144:1941-1953. DOI: 10.1002/ijc.31937
  2. 2. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Medicine. 2006;3:e442. DOI: 10.1371/journal.pmed.0030442
  3. 3. Zhang W, Bojorquez-Gomez A, Velez DO, Xu G, Sanchez KS, Shen JP. A global transcriptional network connecting noncoding mutations to changes in tumor gene expression. Nature Genetics. 2018;50:613-620. DOI: 10.1038/s41588-018-0091-2
  4. 4. Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, et al. Oncogenic signaling pathways in the cancer genome atlas. Cell. 2018;173:321-337.e310. DOI: 10.1016/j.cell.2018.03.035
  5. 5. Sandoval-Bórquez A, Polakovicova I, Carrasco-Veliz N, Lobos-Gonzalez L, Riquelme I, Carrasco-Avino G, et al. MicroRNA-335-5p is a potential suppressor of metastasis and invasion in gastric cancer. Clinical Epigenetics. 2017;9:114. DOI: 10.1186/s13148-017-0413-8
  6. 6. Yang Y, Liu M, Deng Y, Guo Y, Zhang X, Xiang D, et al. Pretreatment microRNA levels can predict HBsAg clearance in CHB patients treated with pegylated interferon alpha-2a. Virology Journal. 2018;15:73. DOI: 10.1186/s12985-018-0982-y
  7. 7. Anastasiadou E, Jacob LS, Slack FJ. Non-coding RNA networks in cancer. Nature Reviews Cancer. 2018;18:5-18. DOI: 10.1038/nrc.2017.99
  8. 8. Feeley KP, Edmonds MD. Hiding in plain sight: Rediscovering the importance of noncoding RNA in human malignancy. Cancer Research. 2018;78:2149-2158. DOI: 10.1158/0008-5472.can-17-2675
  9. 9. Diamantopoulos MA, Tsiakanikas P, Scorilas A. Non-coding RNAs: The riddle of the transcriptome and their perspectives in cancer. Annals of Translational Medicine. 2018;6:241. DOI: 10.21037/atm.2018.06.10
  10. 10. Weng W, Li H, Goel A. Piwi-interacting RNAs (piRNAs) and cancer: Emerging biological concepts and potential clinical implications. Biochimica et Biophysica Acta, Reviews on Cancer. 2019;1871:160-169. DOI: 10.1016/j.bbcan.2018.12.005
  11. 11. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391:806-811. DOI: 10.1038/35888
  12. 12. Singh A, Trivedi P, Jain NK. Advances in siRNA delivery in cancer therapy. Artificial Cells, Nanomedicine, and Biotechnology. 2018;46:274-283. DOI: 10.1080/21691401.2017.1307210
  13. 13. Bartel DP. Metazoan microRNAs. Cell. 2018;173:20-51. DOI: 10.1016/j.cell.2018.03.006
  14. 14. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843-854
  15. 15. Kozomara A, Birgaoanu M, Griffiths-Jones S. miRBase: From microRNA sequences to function. Nucleic Acids Research. 2019;47:D155-D162. DOI: 10.1093/nar/gky1141
  16. 16. Oliveto S, Mancino M, Manfrini N, Biffo S. Role of microRNAs in translation regulation and cancer. World Journal of Biological Chemistry. 2017;8:45-56. DOI: 10.4331/wjbc.v8.i1.45
  17. 17. Rupaimoole R, Slack FJ. MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases. Nature Reviews Drug Discovery. 2017;16:203-222. DOI: 10.1038/nrd.2016.246
  18. 18. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834-838. DOI: 10.1038/nature03702
  19. 19. Williams AE, Moschos SA, Perry MM, Barnes PJ, Lindsay MA. Maternally imprinted microRNAs are differentially expressed during mouse and human lung development. Developmental Dynamics: An Official Publication of the American Association of the Anatomists. 2007;236:572-580. DOI: 10.1002/dvdy.21047
  20. 20. Luo LJ, Wang DD, Wang J, Yang F, Tang JH. Diverse roles of miR-335 in development and progression of cancers. Tumour Biology. 2016;37:15399-15410. DOI: 10.1007/s13277-016-5385-3
  21. 21. Rodriguez A, Griffiths-Jones S, Ashurst JL, Bradley A. Identification of mammalian microRNA host genes and transcription units. Genome Research. 2004;14:1902-1910. DOI: 10.1101/gr.2722704
  22. 22. Peng W, Chen Y, Luo X, Shan N, Lan X, Olson D, et al. DNA methylation-associated repression of MEST/PEG1 expression contributes to the invasion of extravillous trophoblast cells. Placenta. 2016;46:92-101. DOI: 10.1016/j.placenta.2016.08.093
  23. 23. Weber MJ. New human and mouse microRNA genes found by homology search. The FEBS Journal. 2005;272:59-73. DOI: 10.1111/j.1432-1033.2004.04389.x
  24. 24. Li Z, Li D, Zhang G, Xiong J, Jie Z, Cheng H, et al. Methylation-associated silencing of microRNA-335 contributes tumor cell invasion and migration by interacting with RASA1 in gastric cancer. American Journal of Cancer Research. 2014;4:648-662
  25. 25. Zhang JK, Li YS, Zhang CD, Dai DQ. Up-regulation of CRKL by microRNA-335 methylation is associated with poor prognosis in gastric cancer. Cancer Cell International. 2017;17:28. DOI: 10.1186/s12935-017-0387-9
  26. 26. Png KJ, Yoshida M, Zhang XH, Shu W, Lee H, Rimner A, et al. MicroRNA-335 inhibits tumor reinitiation and is silenced through genetic and epigenetic mechanisms in human breast cancer. Genes & Development. 2011;25:226-231. DOI: 10.1101/gad.1974211
  27. 27. Dohi O, Yasui K, Gen Y, Takada H, Endo M, Tsuji K, et al. Epigenetic silencing of miR-335 and its host gene MEST in hepatocellular carcinoma. International Journal of Oncology. 2013;42:411-418. DOI: 10.3892/ijo.2012.1724
  28. 28. Peters Y, Al-Kaabi A, Shaheen NJ, Chak A, Blum A, Souza RF, et al. Barrett oesophagus. Nature Reviews Disease Primers. 2019;5:35. DOI: 10.1038/s41572-019-0086-z
  29. 29. Xi T, Zhang G. Epigenetic regulation on the gene expression signature in esophagus adenocarcinoma. Pathology, Research and Practice. 2017;213:83-88. DOI: 10.1016/j.prp.2016.12.007
  30. 30. Owen GI, Pinto MP, Retamal IN, Fernadez MF, Cisternas B, Mondaca S, et al. Chilean gastric cancer task force: A study protocol to obtain a clinical and molecular classification of a cohort of gastric cancer patients. Medicine. 2018;97:e0419. DOI: 10.1097/md.0000000000010419
  31. 31. Lin SJ, Gagnon-Bartsch JA, Tan IB, Earle S, Ruff L, Pettinger K, et al. Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas. Gut. 2015;64:1721-1731. DOI: 10.1136/gutjnl-2014-308252
  32. 32. Ossandon FJ, Villarroel C, Aguayo F, Santibanez E, Oue N, Yasui W, et al. In silico analysis of gastric carcinoma serial analysis of gene expression libraries reveals different profiles associated with ethnicity. Molecular Cancer. 2008;7:22. DOI: 10.1186/1476-4598-7-22
  33. 33. Xu Y, Zhao F, Wang Z, Song Y, Luo Y, Zhang X, et al. MicroRNA-335 acts as a metastasis suppressor in gastric cancer by targeting Bcl-w and specificity protein 1. Oncogene. 2012;31:1398-1407. DOI: 10.1038/onc.2011.340
  34. 34. Yang B, Huang J, Liu H, Guo W, Li G. miR-335 directly, while miR-34a indirectly modulate survivin expression and regulate growth, apoptosis, and invasion of gastric cancer cells. Tumour Biology. 2016;37:1771-1779. DOI: 10.1007/s13277-015-3951-8
  35. 35. Yan Z, Xiong Y, Xu W, Gao J, Cheng Y, Wang Z, et al. Identification of hsa-miR-335 as a prognostic signature in gastric cancer. PLoS One. 2012;7:e40037. DOI: 10.1371/journal.pone.0040037
  36. 36. Mjelle R, Sjursen W, Thommesen L, Saetrom P, Hofsli E. Small RNA expression from viruses, bacteria and human miRNAs in colon cancer tissue and its association with microsatellite instability and tumor location. BMC Cancer. 2019;19:161. DOI: 10.1186/s12885-019-5330-0
  37. 37. Tsikitis VL, Potter A, Mori M, Buckmeier JA, Preece CR, Harrington CA, et al. MicroRNA signatures of colonic polyps on screening and histology. Cancer Prevention Research. 2016;9:942-949. DOI: 10.1158/1940-6207.capr-16-0086
  38. 38. Lu Y, Yang H, Yuan L, Liu G, Zhang C, Hong M, et al. Overexpression of miR-335 confers cell proliferation and tumour growth to colorectal carcinoma cells. Molecular and Cellular Biochemistry. 2016;412:235-245. DOI: 10.1007/s11010-015-2630-9
  39. 39. Sun Z, Zhang Z, Liu Z, Qiu B, Liu K, Dong G. MicroRNA-335 inhibits invasion and metastasis of colorectal cancer by targeting ZEB2. Medical Oncology. 2014;31:982. DOI: 10.1007/s12032-014-0982-8
  40. 40. Hartke J, Johnson M, Ghabril M. The diagnosis and treatment of hepatocellular carcinoma. Seminars in Diagnostic Pathology. 2017;34:153-159. DOI: 10.1053/j.semdp.2016.12.011
  41. 41. Sebastiani G, Gkouvatsos K, Pantopoulos K. Chronic hepatitis C and liver fibrosis. World Journal of Gastroenterology. 2014;20:11033-11053. DOI: 10.3748/wjg.v20.i32.11033
  42. 42. Wang G, Dong F, Xu Z, Sharma S, Hu X, Chen D, et al. MicroRNA profile in HBV-induced infection and hepatocellular carcinoma. BMC Cancer. 2017;17:805. DOI: 10.1089/dna.2017.3926
  43. 43. Tariq NU, McNamara MG, Valle JW. Biliary tract cancers: Current knowledge, clinical candidates and future challenges. Cancer Management and Research. 2019;11:2623-2642. DOI: 10.2147/cmar.s157092
  44. 44. Chandra V, Kim JJ, Mittal B, Rai R. MicroRNA aberrations: An emerging field for gallbladder cancer management. World Journal of Gastroenterology. 2016;22:1787-1799. DOI: 10.3748/wjg.v22.i5.1787
  45. 45. Peng HH, Zhang YD, Gong LS, Liu WD, Zhang Y. Increased expression of microRNA-335 predicts a favorable prognosis in primary gallbladder carcinoma. OncoTargets and Therapy. 2013;6:1625-1630. DOI: 10.2147/ott.s53030
  46. 46. Cao J, Zhang Y, Yang J, He S, Li M, Yan S, et al. NEAT1 regulates pancreatic cancer cell growth, invasion and migration though mircroRNA-335-5p/c-met axis. American Journal of Cancer Research. 2016;6:2361-2374
  47. 47. Davis CA, Hitz BC, Sloan CA, Chan ET, Davidson JM, Gabdank I, et al. The encyclopedia of DNA elements (ENCODE): Data portal update. Nucleic Acids Research. 2018;46:D794-d801. DOI: 10.1093/nar/gkx1081
  48. 48. Salviano-Silva A, Lobo-Alves SC, Almeida RC, Malheiros D, Petzl-Erler ML. Besides pathology: Long non-coding RNA in cell and tissue homeostasis. Noncoding RNA. 2018;4:3. DOI: 10.3390/ncrna4010003
  49. 49. Gutschner T, Diederichs S. The hallmarks of cancer: A long non-coding RNA point of view. RNA Biology. 2012;9:703-719. DOI: 10.4161/rna.20481
  50. 50. Bhan A, Soleimani M, Mandal SS. Long noncoding RNA and cancer: A new paradigm. Cancer Research. 2017;77:3965-3981. DOI: 10.1158/0008-5472.can-16-2634
  51. 51. Gao S, Zhao ZY, Wu R, Zhang Y, Zhang ZY. Prognostic value of long noncoding RNAs in gastric cancer: A meta-analysis. OncoTargets and Therapy. 2018;11:4877-4891. DOI: 10.2147/ott.s169823
  52. 52. Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. A ceRNA hypothesis: The Rosetta stone of a hidden RNA language? Cell. 2011;146:353-358. DOI: 10.1016/j.cell.2011.07.014
  53. 53. Thomson DW, Dinger ME. Endogenous microRNA sponges: Evidence and controversy. Nature Reviews Genetics. 2016;17:272-283. DOI: 10.1038/nrg.2016.20
  54. 54. Chen S, Xia X. Long noncoding RNA NEAT1 suppresses sorafenib sensitivity of hepatocellular carcinoma cells via regulating miR-335-c-Met. Journal of Cellular Physiology. 2019;234:14999-15009. DOI: 10.1002/jcp.27567
  55. 55. Li H, Zhu H, Zhou Y, Wang H, Niu Z, Shen Y, et al. Long non-coding RNA MSTO2P promotes the proliferation and colony formation in gastric cancer by indirectly regulating miR-335 expression. Tumour Biology. 2017;39:1010428317705506. DOI: 10.1177/1010428317705506
  56. 56. Wang H, Zhang M, Sun G. Long non-coding RNA NEAT1 regulates the proliferation, migration and invasion of gastric cancer cells via targeting miR-335-5p/ROCK1 axis. Die Pharmazie. 2018;73:150-155. DOI: 10.1691/ph.2018.7877
  57. 57. Zhang LL, Zhang LF, Guo XH, Zhang DZ, Yang F, Fan YY. Downregulation of miR-335-5p by long noncoding RNA ZEB1-AS1 in gastric cancer promotes tumor proliferation and invasion. DNA and Cell Biology. 2018;37:46-52. DOI: 10.1089/dna.2017.3926
  58. 58. Kang C, Song JJ, Lee J, Kim MY. Epigenetics: An emerging player in gastric cancer. World Journal of Gastroenterology. 2014;20:6433-6447. DOI: 10.3748/wjg.v20.i21.6433
  59. 59. Llinas P, Le Du MH, Gardsvoll H, Dano K, Ploug M, Gilquin B, et al. Crystal structure of the human urokinase plasminogen activator receptor bound to an antagonist peptide. The EMBO Journal. 2005;24:1655-1663. DOI: 10.1038/sj.emboj.7600635
  60. 60. Lund IK, Illemann M, Thurison T, Christensen IJ, Hoyer-Hansen G. uPAR as anti-cancer target: Evaluation of biomarker potential, histological localization, and antibody-based therapy. Current Drug Targets. 2011;12:1744-1760
  61. 61. Nowicki TS, Zhao H, Darzynkiewicz Z, Moscatello A, Shin E, Schantz S, et al. Downregulation of uPAR inhibits migration, invasion, proliferation, FAK/PI3K/Akt signaling and induces senescence in papillary thyroid carcinoma cells. Cell Cycle. 2011;10:100-107. DOI: 10.4161/cc.10.1.14362
  62. 62. Hong SI, Park IC, Son YS, Lee SH, Kim BG, Lee JI, et al. Expression of urokinase-type plasminogen activator, its receptor, and its inhibitor in gastric adenocarcinoma tissues. Journal of Korean Medical Science. 1996;11:33-37. DOI: 10.3346/jkms.1996.11.1.33
  63. 63. Khoi PN, Xia Y, Lian S, Kim HD, Kim DH, Joo YE, et al. Cadmium induces urokinase-type plasminogen activator receptor expression and the cell invasiveness of human gastric cancer cells via the ERK-1/2, NF-kappaB, and AP-1 signaling pathways. International Journal of Oncology. 2014;45:1760-1768. DOI: 10.3892/ijo.2014.2558
  64. 64. Okazaki M, Takeshita S, Kawai S, Kikuno R, Tsujimura A, Kudo A, et al. Molecular cloning and characterization of OB-cadherin, a new member of cadherin family expressed in osteoblasts. The Journal of Biological Chemistry. 1994;269:12092-12098
  65. 65. van Roy F. Beyond E-cadherin: Roles of other cadherin superfamily members in cancer. Nature Reviews. Cancer. 2014;14:121-134. DOI: 10.1038/nrc3647
  66. 66. Bellahcene A, Castronovo V, Ogbureke KU, Fisher LW, Fedarko NS. Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): Multifunctional proteins in cancer. Nature Reviews Cancer. 2008;8:212-226. DOI: 10.1038/nrc2345
  67. 67. Vecchi M, Nuciforo P, Romagnoli S, Confalonieri S, Pellegrini C, Serio G, et al. Gene expression analysis of early and advanced gastric cancers. Oncogene. 2007;26:4284-4294. DOI: 10.1038/sj.onc.1210208
  68. 68. Sapari NS, Loh M, Vaithilingam A, Soong R. Clinical potential of DNA methylation in gastric cancer: A meta-analysis. PLoS One. 2012;7:e36275. DOI: 10.1371/journal.pone.0036275
  69. 69. Ma J, Hong L, Chen Z, Nie Y, Fan D. Epigenetic regulation of microRNAs in gastric cancer. Digestive Diseases and Sciences. 2014;59:716-723. DOI: 10.1007/s10620-013-2939-8

Written By

Pablo M. Santoro, Alejandra Sandoval-Bórquez and Alejandro H. Corvalan

Submitted: 26 February 2019 Reviewed: 29 July 2019 Published: 07 October 2019