|Year : 2016 | Volume
| Issue : 2 | Page : 1070-1074
The role low microRNA-335 expression in prognosis prediction of human cancers
Du He, Li Hong, Wenjun Guo
Department of Gynaecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, P.R. China
|Date of Web Publication||25-Jul-2016|
Department of Gynaecology and Obstetrics, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, Hubei Province
Source of Support: None, Conflict of Interest: None
Introduction: MicroRNA-335 (miR-335) serves as one of the known miRs in human cancers, however, its prognostic role has yet been settled down. The present research is formed to discuss whether or not miR-335 could be identified as a prognostic biomarker of human cancers.
Materials and Methods: All eligible references from four main databases were included in this study based on the inclusion/exclusion criteria. Moreover, we performed a meta-analysis to explore the prognostic role of miR-335 in human cancers.
Results: Finally, we found eight articles which met the inclusion/exclusion criteria, involving 1098 subjects. miR-335 is deregulated in human cancer tissues compared to noncancerous tissues. We found that the pooled hazard ratios with 95% confidence interval were 1.35 (1.00, 1.83) for overall survival and 1.54 (0.36, 6.68) for relapse-free survival.
Conclusion: The prognostic value of the low miR-335 expression cannot be completely decided based on the present evidences. More related clinical research should be implemented to further study the prognostic role of miR-335 in human cancers.
Keywords: Human cancers, meta-analysis, microRNA-335, prognosis
|How to cite this article:|
He D, Hong L, Guo W. The role low microRNA-335 expression in prognosis prediction of human cancers. J Can Res Ther 2016;12:1070-4
| > Introduction|| |
There has an alarming trend that the global incidence of human cancers is increasing rapidly, especially in developing countries. Various kinds of therapeutic strategy were implemented to try to improve the cancer-associated survival. However, the present cancer diagnosis and treatments are far from perfect. Recently, Allemani et al. have reported their worldwide surveillance results of cancer survival. They found that even though a 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries, other types of cancer still remain fatal such as liver and lung cancer.
The regular thinking of cancer researchers is that whether or not a tumor biomarker could be recognized to contribute to early diagnosis, treatment, and prognosis. Therefore, numerous tumor biomarkers are identified, and some of them are already play a role in clinical diagnosis and treatments such as alpha fetal protein in liver cancer and prostate-specific antigen in prostate cancer. However, the more cases are that the accuracy of biomarkers is uncertain, especially in microRNAs (miRs). As small RNA molecules (~22 nucleotides long), miRs can negatively impact their target gene expression through posttranscriptional way. By means of binding to target mRNAs, miRs can result in deregulation of mRNAs' stabilities and translation. Recent studies  revealed that miRs were correlated with either tumorigenesis or tumor suppressor. For example, a meta-analysis  insisted that deregulation of miR-100 is correlated with human cancer overall survival (OS) and could be a prognostic biomarker.
However, the prognostic role of miR-335 is still remain contradictory. miR-335 has been found upregulated in glioma  and myeloma, while deregulated in breast cancer cells, gastric cancer cells, and ovarian cancer cells. Moreover, the completely different prognostic values of miR-335 were discovered in various types of human cancer. Thus, it is still unknown whether or not miR-335 could be serve as a prognostic biomarker in human cancers. Therefore, in this study, we examined the relationship between miR-335 expression and human cancer prognosis by means of meta-analysis.
| > Materials and Methods|| |
Four main databases were selected to retrieve including PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and Cochrane library. Moreover, the reference part of included articles has also been artificial retrieved. The retrieval strategy involving the following keywords variably combined by “miR-335,” “cancer,” “tumor,” “carcinoma,” “survival outcomes,” and “prognosis.”
(I) The target disease is human cancer; (II) the prognostic role of miR-335 was studied including OS, progression-free survival, or disease-free survival.
(I) These article types are excluded: Review, letter, laboratory research, or mechanism study; (II) the article is duplicated; (III) the research is a cohort study or have no control group; (IV) it lacked critical data for meta-analysis such as hazard ratio (HR) or Kaplan–Meier (K-M) curves.
Two researchers were distributed to screen the above references according to the inclusion/exclusion criteria, independently. Any disagreement was resolved by consensus. The original data involving the expression statue of miR-335 in tumor tissues and noncancerous tissues, the K-M curves or HR and 95% confidence interval (95% CI) of survival outcomes. Furthermore, the baseline data were extracted by the other two researchers independently. We think that multivariate cox hazard regression analysis data are the first choice, if cannot obtained, univariate Cox hazard regression analysis or K-M survival curves of survival outcomes were instead. The K-M curves' data were extracted by Engauge Digitizer 4.1 (http://sourceforge.net).
The meta-analysis was implemented by STATA 11.0 (STATA Corporation, College Station, TX, USA). Heterogeneity was defined as P < 0.05 or I2 ≥65%. If heterogeneity was fine (P ≥ 0.05, I2 <65%), a fixed effect model was used to calculate the pooled HRs. Contrarily, a random effect model was used to calculate the pooled HRs, if the subgroup analysis was unable to decrease the heterogeneity. If the pooled HR >1 and the 95% CI exclude 1, it indicated a significant worse outcome for the case group compared to the control group. If the pooled standardized mean difference (SMD) >0 and the 95% CI exclude 0, it indicated a significant outcome for the case group compared to the control group. The publication bias was tested by Begg's test and Egger's test, P < 0.05 indicating that potential publication bias existed.
| > Results|| |
After primary retrieval, 91 references were incorporated into our primary filtration, including 64 references in Web of Science, 19 references in PubMed, five references in CNKI, and zero references in Cochrane library. Furthermore, artificial retrieval included three references. Through later filtration of abstracts, 77 references were excluded because among them 32 references were just associated with the mechanism, 12 references were not related to the prognosis of miR-335, 32 references were review or letter and others. Fourteen references were selected for finally full-text review. After further filtration, five references were excluded because of duplication. Nine references were finally retrieved as qualified articles, including a total of 1098 subjects with a median number of 122 subjects per study. The concrete step of our filtration was presented in [Figure 1]. The prognostic role of miR-335 was discussed in eight types of human cancer including glioma, colorectal cancer (CRC), pediatric acute myeloid leukemia, prostate cancer, cervical cancer, primary gallbladder carcinoma, gastric cancer, and ovarian cancer., The detailed characteristics of included articles are listed in [Table 1].
The expression statue of miR-335 in tumor tissues and noncancerous tissues.
Seven of nine included references reported the comparison data of miR-335 expression level between tumor tissues and noncancerous tissues [Table 2]. Among them, two researchers reported the upregulation of miR-335 in tumor tissues while the other five studies found that miR-335 was significantly deregulated in tumor tissues compared to noncancerous tissues. After pooled the reported data by meta-analysis, we found that the pooled SMD (95% CI) is 2.39 (0.16, 4.62) [Figure 2].
|Table 2: The expression statue of microRNA-335 in noncancerous tissues and cancer tissues|
Click here to view
|Figure 2: The meta-analysis of expression difference of microRNA-100 between noncancerous tissues and cancer tissues|
Click here to view
Prognostic role of microRNA-335 in human cancers
All nine references listed the correlation between miR-335 expression and human cancer OS, and three references listed the correlation between miR-335 expression and human cancer relapse-free survival (RFS) or metastasis-free survival (MFS). For easy to analysis, we defined RFS to include RFS and MFS. The heterogeneity has not been found in the nine references, and the pooled HR (95% CI) of OS has been calculated by a fixed effect model. However, the heterogeneity was existed among these three studies, and the pooled HR with 95% CI of RFS has been calculated by a random effect model. We found that the pooled HR (95% CI) of OS and the pooled HR with 95% CI of RFS were 1.35 (1.00, 1.83) [Figure 3] and 1.54 (0.36, 6.68) [Figure 4], respectively.
|Figure 3: The pooled hazard ratio (95% confidence interval) summary the relationship between low microRNA-335 expression and overall survival of human cancers through a fix effect model|
Click here to view
|Figure 4: The pooled hazard ratio (95% confidence interval) summary the relationship between low microRNA-335 expression and relapse-free survival of human cancers through a random effect model|
Click here to view
Begg's funnel plot and Egger's test were used to evaluate the publication bias. The P value of Egger's test (P = 0.684) did not detect any evidence of publication bias, even though slight publication bias has been discovered by Begg's funnel plot [Figure 5]. However, we have to warn that a poor sensitivity of Begg's funnel plot and Egger's test when the number of eligible articles is <20.
| > Discussion|| |
Recent years, miRNAs have been found to play a role in multiple human diseases including cancers, because they have great power to impact gene expression through posttranscriptional way. Hitherto, various kinds of miRs have been found to correlate with tumorigenesis or tumor progression. For example, researchers  found that miR-21 was upregulated in glioma compared with normal brain and related to cell apoptosis, tumor proliferation, invasiveness, and migration. Furthermore, many miRs have been found to correlate to tumor prognosis such as miR-34, miR-375, miR-21, miR-210, and miR-218.
As a potential tumor-related miR, the gene locus of miR-335 is on chromosome 7q32.2. However, expression patterns and functional role of miR-335 in different types of human cancers are controversial. Yan et al. found that high miR-335 expression has the potential correlation with high-frequency recurrence and poor prognosis of gastric cancer patients. Contrarily, Sun et al. implied that CRC patients with low miR-335 expression had a poor OS. Furthermore, they found that upregulation of miR-335 inhibited CRC cell migration and invasion in vitro and lung and liver metastasis in vivo, through targeting ZEB2.
Accordingly, whether miR-335 acts as a tumor suppressor or an oncogene remains obscured. Thus, in this study, we initiated a comprehensive meta-analysis to explore the relationship between miR-335 expression and human cancer prognosis. According to nine final included researches, we primarily examined the expression difference of miR-335 between tumor tissues and noncancerous tissues. We found that miR-335 was significantly deregulated in tumor tissues when compared to noncancerous tissues. Furthermore, we discovered that human cancer patients with low miR-335 expression have a poorer OS than patients with high miR-335 expression, we did not find any significant difference between low miR-335 expression and RFS of patients. The nonconformity between the pooled HR (95% CI) of OS and RFS has weakened the strengthen of our meta-evidences.
In addition, there have several factors that might weaken the strength of our evidences. Initially, the associated articles which studied the prognostic role of miR-335 in human cancers were limited, since the number of included references was only nine. Second, the amount of patients included in each clinical research is inadequate that makes us difficult to obtain sufficient miR-335 expression data. Third, because of the differences in baseline characters of population, the tumor types, the cut-off value, follow-up, and so on, the heterogeneity existed in our meta-analysis. Consequently, we strongly suggest implementing more clinical researches to further explore the relationship between miR-335 expression and human cancer prognosis. Especially, we should further explore the role of miR-335 in different types of human cancer. Because we cannot make sure that whether or not miR-335 play the same role in various types of human cancer.
Overall, this meta-analysis has displayed that the present research statue of low miR-335 expression in human cancer prognosis. However, the present evidences cannot sufficiently support that deregulation of miR-335 is associated with poor survival outcome in human cancer patients. More related clinical research should be implemented to further study the prognostic role of miR-335 in human cancers.
| > References|| |
Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, et al
. Global surveillance of cancer survival 1995-2009: Analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet 2015;385:977-1010.
Chuang JC, Jones PA. Epigenetics and microRNAs. Pediatr Res 2007;61(5 Pt 2):24R-9R.
Liu C. The role of microRNAs in tumors. Arch Pharm Res 2013;36:1169-77.
Chen J, Zheng B, Wang C, Chen Y, Du C, Zhao G, et al
. Prognostic role of microRNA-100 in various carcinomas: Evidence from six studies. Tumour Biol 2014;35:3067-71.
Shu M, Zheng X, Wu S, Lu H, Leng T, Zhu W, et al
. Targeting oncogenic miR-335 inhibits growth and invasion of malignant astrocytoma cells. Mol Cancer 2011;10:59.
Ronchetti D, Lionetti M, Mosca L, Agnelli L, Andronache A, Fabris S, et al
. An integrative genomic approach reveals coordinated expression of intronic miR-335, miR-342, and miR-561 with deregulated host genes in multiple myeloma. BMC Med Genomics 2008;1:37.
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 Dev 2011;25:226-31.
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;31:1398-407.
Sorrentino A, Liu CG, Addario A, Peschle C, Scambia G, Ferlini C. Role of microRNAs in drug-resistant ovarian cancer cells. Gynecol Oncol 2008;111:478-86.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.
Jiang J, Sun X, Wang W, Jin X, Bo X, Li Z, et al
. Tumor microRNA-335 expression is associated with poor prognosis in human glioma. Med Oncol 2012;29:3472-7.
Sun Z, Zhang Z, Liu Z, Qiu B, Liu K, Dong G. MicroRNA-335 inhibits invasion and metastasis of colorectal cancer by targeting ZEB2. Med Oncol 2014;31:982.
Lin X, Wang Z, Zhang R, Feng W. High serum microRNA-335 level predicts aggressive tumor progression and unfavorable prognosis in pediatric acute myeloid leukemia. Clin Transl Oncol 2015;17:358-64.
Xiong SW, Lin TX, Xu KW, Dong W, Ling XH, Jiang FN, et al
. MicroRNA-335 acts as a candidate tumor suppressor in prostate cancer. Pathol Oncol Res 2013;19:529-37.
Wang C, Jiang T. MicroRNA-335 represents an independent prognostic marker in cervical cancer. Tumour Biol 2015;36:5825-30.
Peng HH, Zhang YD, Gong LS, Liu WD, Zhang Y. Increased expression of microRNA-335 predicts a favorable prognosis in primary gallbladder carcinoma. Onco Targets Ther 2013;6:1625-30.
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.
Cao J, Cai J, Huang D, Han Q, Chen Y, Yang Q, et al
. miR-335 represents an independent prognostic marker in epithelial ovarian cancer. Am J Clin Pathol 2014;141:437-42.
Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 2005;65:6029-33.
Wang L, Yu J, Xu J, Zheng C, Li X, Du J. The analysis of microRNA-34 family expression in human cancer studies comparing cancer tissues with corresponding pericarcinous tissues. Gene 2015;554:1-8.
Shao Y, Geng Y, Gu W, Huang J, Ning Z, Pei H. Prognostic significance of microRNA-375 downregulation in solid tumors: A meta-analysis. Dis Markers 2014;2014:626185.
Zhu W, Xu B. MicroRNA-21 identified as predictor of cancer outcome: A meta-analysis. PLoS One 2014;9:e103373.
Li M, Ma X, Li M, Zhang B, Huang J, Liu L, et al
. Prognostic role of microRNA-210 in various carcinomas: A systematic review and meta-analysis. Dis Markers 2014;2014:106197.
Gao Y, Liu Y, Liu GL, Ran LK, Zeng F, Wu JY, et al
. Association between the pre-mir-218 polymorphism and cancer risk in the Chinese population: A meta-analysis. Asian Pac J Cancer Prev 2014;15:2517-22.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]