Abstract
MicroRNA (miR) is a type of short non-coding RNA comprising 21–25 nucleotides. While it has been researched widely, its relationship with cancer was clarified recently and it was found to play a significant role in the development and progression of cancer. Furthermore, miR can remain stable for relatively long periods in the blood by being present in exosomes (extracellular microvesicles) or by forming a complex with the Ago2 protein, which gives rise to cancer-specific miR. It is known that miR can indicate the presence and extent of cancer progression. Several reports have proved that miR in urine and saliva is detected in urinary and oral cancer, respectively, and recent studies have also shown it to be present in cases of gastroenterological cancer, showing evidence of it being a biomarker for cancer. To gather further knowledge on this topic, this review aims to summarize the usefulness of urinary and salivary miR as a biomarker for gastroenterological cancer and discuss its existence, stability mechanism, and direction of future research. The findings will be relevant for physicians and oncologists who routinely treat patients with gastric cancers.
Similar content being viewed by others
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Schochter F, Friedl TWP, deGregorio A et al (2019) Are circulating tumor cells (CTCs) ready for clinical use in breast cancer? An overview of completed and ongoing trials using CTCs for clinical treatment decisions. Cells 8:1412
Lustberg MB, Stover DG, Chalmers JJ (2018) Implementing liquid biopsies in clinical trials: state of affairs, opportunities, and challenges. Cancer J 24:61–64
Ignatiadis M, Rack B, Rothé F et al (2016) Liquid biopsy-based clinical research in early breast cancer: the EORTC 90091–10093 treat CTC trial. Eur J Cancer 63:97–104
Alunni-Fabbroni M, Rönsch K, Huber T et al (2019) Circulating DNA as prognostic biomarker in patients with advanced hepatocellular carcinoma: a translational exploratory study from the SORAMIC trial. J Transl Med 17:328
Nicholls JM, Lee VH, Chan SK et al (2019) Negative plasma Epstein-Barr virus DNA nasopharyngeal carcinoma in an endemic region and its influence on liquid biopsy screening programmes. Br J Cancer 121:690–698
Wei B, Zhao C, Li J et al (2019) Combined plasma and tissue genotyping of EGFR T790M benefits NSCLC patients: a real-world clinical example. Mol Oncol 13:1226–1234
Amelio I, Bertolo R, Bove P et al (2020) Liquid biopsies and cancer omics. Cell Death Discov 6:131
Sacco A, Forgione L, Carotenuto M et al (2020) Circulating tumor DNA testing opens new perspectives in melanoma management. Cancers (Basel) 12:2914
Aggarwal C, Rolfo CD, Oxnard GR et al (2021) Strategies for the successful implementation of plasma-based NSCLC genotyping in clinical practice. Nat Rev Clin Oncol 18:56–62
Sholl LM, Hirsch FR, Hwang D et al (2020) The promises and challenges of tumor mutation burden as an immunotherapy biomarker: a perspective from the international association for the study of lung cancer pathology committee. J Thorac Oncol 15:1409–1424
Guo R, Luo J, Chang J et al (2020) MET-dependent solid tumours—molecular diagnosis and targeted therapy. Nat Rev Clin Oncol 17:569–587
Melchardt T, Magnes T, Hufnagl C et al (2018) Clonal evolution and heterogeneity in metastatic head and neck cancer—an analysis of the Austrian Study Group of Medical Tumour Therapy study group. Eur J Cancer 93:69–78
Heitzer E, Perakis S, Geigl JB et al (2017) The potential of liquid biopsies for the early detection of cancer. NPJ Precis Oncol 1:36
Asante DB, Calapre L, Ziman M et al (2020) Liquid biopsy in ovarian cancer using circulating tumor DNA and cells: ready for prime time? Cancer Lett 468:59–71
Takeshita N, Hoshino I, Mori M et al (2013) Serum microRNA expression profile: miR-1246 as a novel diagnostic and prognostic biomarker for oesophageal squamous cell carcinoma. Br J Cancer 108:644–652
Hoshino I, Ishige F, Iwatate Y et al (2020) Usefulness of serum miR-1246/miR-106b ratio in patients with esophageal squamous cell carcinoma. Oncol Lett 20:350
Hoshino I, Nabeya Y, Takiguchi N et al (2020) Prognostic impact of p53 and/or NY-ESO-1 autoantibody induction in patients with gastroenterological cancers. Ann Gastroenterol Surg 4:275–282
Hoshino I, Nabeya Y, Takiguchi N et al (2020) Inducing multiple antibodies to treat squamous cell esophageal carcinoma. BMC Cancer 20:1007
Bhawal R, Oberg AL, Zhang S et al (2020) Challenges and opportunities in clinical applications of blood-based proteomics in cancer. Cancers (Basel) 12:2428
Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114
Liu J, Carmell MA, Rivas FV et al (2004) Argonaute2 is the catalytic engine of mammalian RNAi. Science 305:1437–1441
Dykxhoorn DM (2010) MicroRNAs and metastasis: little RNAs go a long way. Cancer Res 70:6401–6406
Kong YW, Ferland-McCollough D, Jackson TJ et al (2012) microRNAs in cancer management. Lancet Oncol 13:e249-258
Isozaki Y, Hoshino I, Akutsu Y et al (2015) Usefulness of microRNA-375 as a prognostic and therapeutic tool in esophageal squamous cell carcinoma. Int J Oncol 46:1059–1066
Kano M, Seki N, Kikkawa N et al (2010) miR-145, miR-133a and miR-133b: Tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma. Int J Cancer 127:2804–2814
Sohel MMH (2020) Circulating microRNAs as biomarkers in cancer diagnosis. Life Sci 248:117473
Hoshino I, Matsubara H (2013) MicroRNAs in cancer diagnosis and therapy: from bench to bedside. Surg Today 43:467–478
Turchinovich A, Weiz L, Langheinz A et al (2011) Characterization of extracellular circulating microRNA. Nucleic Acids Res 39:7223–7233
Lakshmi S, Hughes TA, Priya S (2020) Exosomes and exosomal RNAs in breast cancer: a status update. Eur J Cancer 144:252–268
Cochetti G, Cari L, Nocentini G et al (2020) Detection of urinary miRNAs for diagnosis of clear cell renal cell carcinoma. Sci Rep 10:21290
Outeiro-Pinho G, Barros-Silva D, Aznar E et al (2020) MicroRNA-30a-5p(me): a novel diagnostic and prognostic biomarker for clear cell renal cell carcinoma in tissue and urine samples. J Exp Clin Cancer Res 39:98
Deutsch FT, Khoury SJ, Sunwoo JB et al (2020) Application of salivary noncoding microRNAs for the diagnosis of oral cancers. Head Neck 42:3072–3083
Ishige F, Hoshino I, Iwatate Y et al (2020) MIR1246 in body fluids as a biomarker for pancreatic cancer. Sci Rep 10:8723
Yoshizawa N, Sugimoto K, Tameda M et al (2020) miR-3940-5p/miR-8069 ratio in urine exosomes is a novel diagnostic biomarker for pancreatic ductal adenocarcinoma. Oncol Lett 19:2677–2684
Yasui T, Yanagida T, Ito S et al (2017) Unveiling massive numbers of cancer-related urinary-microRNA candidates via nanowires. Sci Adv 3:e1701133
Hoshino I, Ishige F, Iwatate Y et al (2021) Cell-free microRNA-1246 in different body fluids as a diagnostic biomarker for esophageal squamous cell carcinoma. PLoS ONE 16:e0248016
Hasano Ğlu S, Göncü BS, Yücesan E et al (2021) Investigating differential miRNA expression profiling using serum and urine specimens for detecting potential biomarker for early prostate cancer diagnosis. Turk J Med Sci
Wang G, Kwan BC, Lai FM et al (2010) Expression of microRNAs in the urinary sediment of patients with IgA nephropathy. Dis Markers 28:79–86
Wang G, Kwan BC, Lai FM et al (2012) Urinary miR-21, miR-29, and miR-93: novel biomarkers of fibrosis. Am J Nephrol 36:412–418
Vickers KC, Remaley AT (2012) Lipid-based carriers of microRNAs and intercellular communication. Curr Opin Lipidol 23:91–97
Arroyo JD, Chevillet JR, Kroh EM et al (2011) Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci USA 108:5003–5008
Chevillet JR, Kang Q, Ruf IK et al (2014) Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proc Natl Acad Sci USA 111:14888–14893
Jenkins RH, Martin J, Phillips AO et al (2012) Pleiotropy of microRNA-192 in the kidney. Biochem Soc Trans 40:762–767
Beltrami C, Clayton A, Newbury LJ et al (2015) Stabilization of urinary microRNAs by association with exosomes and argonaute 2 protein. Noncoding RNA 1:151–166
Gallo A, Tandon M, Alevizos I et al (2012) The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS ONE 7:e30679
Cheng L, Sun X, Scicluna BJ et al (2014) Characterization and deep sequencing analysis of exosomal and non-exosomal miRNA in human urine. Kidney Int 86:433–444
Ghafouri-Fard S, Shirvani-Farsani Z, Branicki W et al (2020) MicroRNA signature in renal cell carcinoma. Front Oncol 10:596359
Ashrafizadeh M, Hushmandi K, Hashemi M et al (2020) Role of microRNA/epithelial-to-mesenchymal transition axis in the metastasis of bladder cancer. Biomolecules 10(8):1159
Paiva RM, Zauli DAG, Neto BS et al (2020) Urinary microRNAs expression in prostate cancer diagnosis: a systematic review. Clin Transl Oncol 22:2061–2073
De Palma G, Di Lorenzo VF, Krol S et al (2019) Urinary exosomal shuttle RNA: promising cancer diagnosis biomarkers of lower urinary tract. Int J Biol Markers 34:101–107
Dioguardi M, Caloro GA, Laino L et al (2020) Circulating miR-21 as a potential biomarker for the diagnosis of oral cancer: a systematic review with meta-analysis. Cancers (Basel) 12:936
Kao HW, Pan CY, Lai CH et al (2017) Urine miR-21-5p as a potential non-invasive biomarker for gastric cancer. Oncotarget 8:56389–56397
Iwasaki H, Shimura T, Yamada T et al (2019) A novel urinary microRNA biomarker panel for detecting gastric cancer. J Gastroenterol 54:1061–1069
Abdalla MA, Haj-Ahmad Y (2012) Promising candidate urinary MicroRNA biomarkers for the early detection of hepatocellular carcinoma among high-risk hepatitis C virus Egyptian patients. J Cancer 3:19–31
Debernardi S, Massat NJ, Radon TP et al (2015) Noninvasive urinary miRNA biomarkers for early detection of pancreatic adenocarcinoma. Am J Cancer Res 5:3455–3466
Silakit R, Loilome W, Yongvanit P et al (2017) Urinary microRNA-192 and microRNA-21 as potential indicators for liver fluke-associated cholangiocarcinoma risk group. Parasitol Int 66:479–485
Yoshizawa JM, Schafer CA, Schafer JJ et al (2013) Salivary biomarkers: toward future clinical and diagnostic utilities. Clin Microbiol Rev 26:781–791
Michael A, Bajracharya SD, Yuen PS et al (2010) Exosomes from human saliva as a source of microRNA biomarkers. Oral Dis 16:34–38
Park NJ, Zhou H, Elashoff D et al (2009) Salivary microRNA: discovery, characterization, and clinical utility for oral cancer detection. Clin Cancer Res 15:5473–5477
Momen-Heravi F, Trachtenberg AJ, Kuo WP, Cheng YS (2014) Genomewide study of salivary MicroRNAs for detection of oral cancer. J Dent Res 93:86s–93s
Zahran F, Ghalwash D, Shaker O et al (2015) Salivary microRNAs in oral cancer. Oral Dis 21:739–747
Liu CJ, Lin SC, Yang CC et al (2012) Exploiting salivary miR-31 as a clinical biomarker of oral squamous cell carcinoma. Head Neck 34:219–224
Duz MB, Karatas OF, Guzel E et al (2016) Identification of miR-139-5p as a saliva biomarker for tongue squamous cell carcinoma: a pilot study. Cell Oncol (Dordr) 39:187–193
Wiklund ED, Gao S, Hulf T et al (2011) MicroRNA alterations and associated aberrant DNA methylation patterns across multiple sample types in oral squamous cell carcinoma. PLoS ONE 6:e27840
Salazar C, Nagadia R, Pandit P et al (2014) A novel saliva-based microRNA biomarker panel to detect head and neck cancers. Cell Oncol (Dordr) 37:331–338
Matse JH, Yoshizawa J, Wang X et al (2015) Human salivary micro-RNA in patients with parotid salivary gland neoplasms. PLoS ONE 10:e0142264
Xie Z, Chen G, Zhang X et al (2013) Salivary microRNAs as promising biomarkers for detection of esophageal cancer. PLoS ONE 8:e57502
Xie ZJ, Chen G, Zhang XC et al (2012) Saliva supernatant miR-21: a novel potential biomarker for esophageal cancer detection. Asian Pac J Cancer Prev 13:6145–6149
Fendereski M, Zia MF, Shafiee M et al (2017) MicroRNA-196a as a potential diagnostic biomarker for esophageal squamous cell carcinoma. Cancer Invest 35:78–84
Sazanov AA, Kiselyova EV, Zakharenko AA et al (2017) Plasma and saliva miR-21 expression in colorectal cancer patients. J Appl Genet 58:231–237
Rapado-González Ó, Majem B, Álvarez-Castro A et al (2019) A Novel saliva-based miRNA signature for colorectal cancer diagnosis. J Clin Med 8:2029
Gao S, Chen LY, Wang P et al (2014) MicroRNA expression in salivary supernatant of patients with pancreatic cancer and its relationship with ZHENG. Biomed Res Int 1:756347
Humeau M, Vignolle-Vidoni A, Sicard F et al (2015) Salivary MicroRNA in pancreatic cancer patients. PLoS ONE 10:e0130996
Machida T, Tomofuji T, Maruyama T et al (2016) miR-1246 and miR-4644 in salivary exosome as potential biomarkers for pancreatobiliary tract cancer. Oncol Rep 36:2375–2381
Konno M, Koseki J, Asai A et al (2019) Distinct methylation levels of mature microRNAs in gastrointestinal cancers. Nat Commun 10:3888
Acknowledgements
Not applicable.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflicts of interest in association with the present study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Hoshino, I. The usefulness of microRNA in urine and saliva as a biomarker of gastroenterological cancer. Int J Clin Oncol 26, 1431–1440 (2021). https://doi.org/10.1007/s10147-021-01911-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10147-021-01911-1