decoy receptor 3 ( dcr3 )  also referred to as tr6 , m68 , or tnfrsf6b  is a family member of the tumor necrosis factor receptor ( tnfr ) superfamily .
dcr3 has been described in many malignant tumors , such as gastric , hepatocellular , colon , lung , cervical , ovarian , and breast cancer .
a gastrointestinal cancer meta - analysis   reported that overexpression of dcr3 was closely related with clinicopathological features , including tnm stage , grade of differentiation , lymph node metastasis , infiltration degree , and distant metastasis .
the present study is the only meta - analysis on the relationship between dcr3 and malignancies .
female reproductive cancers are among the most common causes of cancer - related death , including breast cancer , ovarian cancer , uterine corpus cancer , and cervical cancer .
some genes and molecules are particularly useful as tracking , identifying , and validating biomarkers for diagnosis and treatment of female reproductive cancers [ 911 ] .
although some studies have explored the role of dcr3 overexpression in cervical cancer , ovarian cancer , and breast cancer , there is still no summary evidence for the association between dcr3 and overall female reproductive cancers .
therefore , we conducted the present meta - analysis to explore the relation between the level of dcr3 , clinicopathological characteristics , and survival of female reproductive cancer patients .
pubmed , wiley online library , web of science , science direct , cochrane central register of controlled trials , google scholar , embase , ovid , lilacs , chinese cnki , chong qing vip , wan fang , and china biology medicine disc were searched up to 30 september 2015 with a random combination of the terms : 
dcr3 or tr6 or m68 or tnfrsf6b ,  cervical or ovarian or ovary or oophoro * or uterine or breast or endometrial or choriocarcinoma or fallopian tube and  cancer or tumor or carcinoma or neoplas * or malignan*. all of the relevant literature , including review articles and potential references , were searched for additional pertinent studies .
articles were searched and screened by 2 investigators independently . in the meta - analysis ,
studies that met the following criteria were eligible : ( 1 ) patients in studies were clearly diagnosed with cervical cancer , ovarian cancer , or breast cancer , as well as other female reproductive cancers ; ( 2 ) studies included were case - control studies and evaluated the relationship between dcr3 expression and clinicopathological features or prognosis in female reproductive cancers ; ( 3 ) the definition of dcr3-positive was tested by immunohistochemistry ( ihc ) method ; ( 4 ) sufficient information of the correlation of dcr3 with clinicopathological features or overall survival time was provided to estimate odds ratio ( or ) and hazard ratio ( hr ) ; and ( 5 ) articles were written in english or chinese .
two independent reviewers read full texts of all eligible studies and extracted relevant data , including author , year , country , cancer type , patient number , test method , clinicopathological parameters ( age , tnm stage , grade of differentiation , and lymph node metastasis ) , and overall survival time .
the heterogeneity between the studies was evaluated by i test . according to the results of heterogeneity analysis
the software engauge digitizer 4.1 was used to extract the survival data from a k - m curve in some articles .
pubmed , wiley online library , web of science , science direct , cochrane central register of controlled trials , google scholar , embase , ovid , lilacs , chinese cnki , chong qing vip , wan fang , and china biology medicine disc were searched up to 30 september 2015 with a random combination of the terms : 
dcr3 or tr6 or m68 or tnfrsf6b ,  cervical or ovarian or ovary or oophoro * or uterine or breast or endometrial or choriocarcinoma or fallopian tube and  cancer or tumor or carcinoma or neoplas * or malignan*. all of the relevant literature , including review articles and potential references , were searched for additional pertinent studies .
articles were searched and screened by 2 investigators independently . in the meta - analysis ,
studies that met the following criteria were eligible : ( 1 ) patients in studies were clearly diagnosed with cervical cancer , ovarian cancer , or breast cancer , as well as other female reproductive cancers ; ( 2 ) studies included were case - control studies and evaluated the relationship between dcr3 expression and clinicopathological features or prognosis in female reproductive cancers ; ( 3 ) the definition of dcr3-positive was tested by immunohistochemistry ( ihc ) method ; ( 4 ) sufficient information of the correlation of dcr3 with clinicopathological features or overall survival time was provided to estimate odds ratio ( or ) and hazard ratio ( hr ) ; and ( 5 ) articles were written in english or chinese .
two independent reviewers read full texts of all eligible studies and extracted relevant data , including author , year , country , cancer type , patient number , test method , clinicopathological parameters ( age , tnm stage , grade of differentiation , and lymph node metastasis ) , and overall survival time .
the heterogeneity between the studies was evaluated by i test . according to the results of heterogeneity analysis
the software engauge digitizer 4.1 was used to extract the survival data from a k - m curve in some articles .
393 were excluded after reviewing the titles and abstracts because these articles described non - human experiments or other cancer types .
then , due to duplication or no report of any relevant outcomes , 26 of the remaining articles were excluded ( figure 1 ) . finally , a total of 12 eligible studies [ 57,1220 ] with 1127 participants were included in this meta - analysis .
the test method of all included studies was only ihc . in this meta - analysis , we assessed the correlation between dcr3 expression and cancer risk , clinicopathological features , and overall survival time of patients with female reproductive cancers .
as shown in figure 2 , overexpression of dcr3 was associated with female reproductive cancer risk ( or=10.69 , 95% ci : 6.3318.05 ) .
furthermore , subgroup analysis showed a consistent trend ; for example , cervical cancer ( or=7.97 , 95% ci : 4.7013.49 ) , ovarian cancer ( or=14.03 , 95% ci : 3.1662.01 ) , and breast cancer ( or=19.35 , 95% ci : 4.4684.03 ) . in analysis of female reproductive cancer patients
regardless of subtype , 3 clinicopathological parameters were found to be significantly associated with overexpression of dcr3 as compared to controls : advanced tnm stage ( or=5.51 , 95% ci : 2.8310.71 ) , poor grade of differentiation ( or=4.16 , 95% ci : 2.287.60 ) , and lymph node metastasis ( or=5.89 , 95% ci : 3.1610.96 ) . in the sub - analysis , a stronger association was found between tnm stage and patients with overexpression of dcr3 in ovarian cancer ( or=6.80 , 95% ci : 2.5018.50 ) than in cervical cancer ( or=4.76 , 95% ci : 1.7413.01 ) or breast cancer ( or=3.73 , 95% ci : 0.7319.09 , figure 3 ) . as shown in figure 4 , for each type of cancer , a concordant relationship
was also observed between dcr3 expression and grade of differentiation : cervical cancer ( or=7.70 , 95% ci : 1.8931.38 ) , ovarian cancer ( or=4.32 , 95% ci : 1.7110.92 ) , and breast cancer ( or=3.56 , 95% ci : 0.7916.00 ) . in sub - analysis of association between patients with different cancers with overexpression of dcr3 and lymph node metastasis ,
cervical cancer had the highest rank ( or=14.64 , 95% ci : 2.4189.04 ) , ovarian cancer was second ( or=5.79 , 95% ci : 1.1329.80 ) , and breast cancer was third ( or=5.10 , 95% ci : 2.2511.59 ) ( figure 5 ) ( all p<0.05 ) . however , as shown in figures 6 and 7 , there was no association between dcr3 overexpression and the age of female reproductive cancer patients ( or=0.85 , 95% ci : 0.511.44 , p=0.554 ) or overall survival time ( or=1.84 , 95% ci : 0.585.83 , p=0.300 ) .
as shown in figure 8 , begg s test suggested that there was no publication bias for risk of female reproductive cancers ( p=0.097 ) , tnm stage ( p=0.559 ) , grade of differentiation ( p=0.156 ) , lymph node metastasis ( p=0.345 ) , age ( p=0.685 ) , or overall survival time ( p=0.394 ) .
393 were excluded after reviewing the titles and abstracts because these articles described non - human experiments or other cancer types .
then , due to duplication or no report of any relevant outcomes , 26 of the remaining articles were excluded ( figure 1 ) . finally , a total of 12 eligible studies [ 57,1220 ] with 1127 participants were included in this meta - analysis .
in this meta - analysis , we assessed the correlation between dcr3 expression and cancer risk , clinicopathological features , and overall survival time of patients with female reproductive cancers .
as shown in figure 2 , overexpression of dcr3 was associated with female reproductive cancer risk ( or=10.69 , 95% ci : 6.3318.05 ) .
furthermore , subgroup analysis showed a consistent trend ; for example , cervical cancer ( or=7.97 , 95% ci : 4.7013.49 ) , ovarian cancer ( or=14.03 , 95% ci : 3.1662.01 ) , and breast cancer ( or=19.35 , 95% ci : 4.4684.03 ) . in analysis of female reproductive cancer patients
regardless of subtype , 3 clinicopathological parameters were found to be significantly associated with overexpression of dcr3 as compared to controls : advanced tnm stage ( or=5.51 , 95% ci : 2.8310.71 ) , poor grade of differentiation ( or=4.16 , 95% ci : 2.287.60 ) , and lymph node metastasis ( or=5.89 , 95% ci : 3.1610.96 ) . in the sub - analysis , a stronger association was found between tnm stage and patients with overexpression of dcr3 in ovarian cancer ( or=6.80 , 95% ci : 2.5018.50 ) than in cervical cancer ( or=4.76 , 95% ci : 1.7413.01 ) or breast cancer ( or=3.73 , 95% ci : 0.7319.09 , figure 3 ) .
as shown in figure 4 , for each type of cancer , a concordant relationship was also observed between dcr3 expression and grade of differentiation : cervical cancer ( or=7.70 , 95% ci : 1.8931.38 ) , ovarian cancer ( or=4.32 , 95% ci : 1.7110.92 ) , and breast cancer ( or=3.56 , 95% ci : 0.7916.00 ) . in sub - analysis of association between patients with different cancers with overexpression of dcr3 and lymph node metastasis ,
cervical cancer had the highest rank ( or=14.64 , 95% ci : 2.4189.04 ) , ovarian cancer was second ( or=5.79 , 95% ci : 1.1329.80 ) , and breast cancer was third ( or=5.10 , 95% ci : 2.2511.59 ) ( figure 5 ) ( all p<0.05 ) .
however , as shown in figures 6 and 7 , there was no association between dcr3 overexpression and the age of female reproductive cancer patients ( or=0.85 , 95% ci : 0.511.44 , p=0.554 ) or overall survival time ( or=1.84 , 95% ci : 0.585.83 , p=0.300 ) .
as shown in figure 8 , begg s test suggested that there was no publication bias for risk of female reproductive cancers ( p=0.097 ) , tnm stage ( p=0.559 ) , grade of differentiation ( p=0.156 ) , lymph node metastasis ( p=0.345 ) , age ( p=0.685 ) , or overall survival time ( p=0.394 ) .
overexpression of dcr3 has been found in many malignant tumors , but , as reported , dcr3 overexpression could not be detected in non - tumor tissues .
studies have shown that dcr3 regulates the activity and differentiation of immune cells , and regulates apoptosis .
first , dcr3 can act as a functional fasl decoy receptor that can bind to fas ligand ( fasl ) and inhibit tumor cell killing .
second , dcr3 might promote tumor growth by attenuating the th1 response and suppressing cell - mediated immunity [ 2325 ] .
( dcr3 fusion protein with immunoglobulin fc ) is able to modulate the expression of a few macrophage markers , including cd14 , cd16 , cd64 , and human leukocyte antigen - dr , suggesting that dcr3 fc might have potent , suppressive effects in down - regulating the host - immune system [ 2628 ] .
fourth , dcr3 can inhibit stromal cell - derived factor 1 chemotaxis of t lymphocytes , thus reducing the organization of cd4 + and cd8 + t lymphocyte infiltration .
fifth , dcr3 induces the apoptosis of dendritic cell ( dc ) via activating pkc - delta and jnk , then up - regulates dr5 to recruit fas - associated death domain ( fadd ) to propagate the apoptotic signals
. the functions and mechanisms might not be completely the same in these 3 types of female reproductive cancers . in breast cancer ,
dcr3 may be regarded as a negative regulator of cancer aggressiveness during development and progression of certain types of breast cancer by using anti - dcr3 monoclonal antibody and anti - dcr3 hammerhead ribozyme transgenes in breast cancer cells .
studies have reported that lymphatic microvessel density ( lmvd ) was elevated in the cancer tissue and lymph node with metastasis , and dcr3 may promote lymph node metastasis of breast cancer by inducing the formation of new lymphatic vessels and increasing opportunities for lymph node metastasis .
wang et al .   reported that after the treatment of dcr3 neutralized with dcr3 antibody , the effect on proliferation of breast cancer cell line was decreased , while addition of fas - l and dcr3 enhanced proliferation .
one of the main mechanisms may be that dcr3 blocks the fas - l - induced apoptosis . in cervical cancer ,
peyre et al .   reported that the number of t cells was significantly lower in peripheral blood of cervical cancer patients , and there was an obvious negative correlation between dcr3 expression and cd3 + , cd4+/cd8+t in peripheral blood .
therefore , they presumed that dcr3 is related to tumor immune escape in patients with cervical cancer
. the expression and distribution of t cells in local tissues of cervical cancer can reflect immune status in the body . in ovarian cancer ,
lin et al .   reported that the proliferation of caov3 cells was significantly decreased by dcr3 sirna in comparison with the normal control group and negative control group , indicating that dcr3 sirna can inhibit the proliferation of ovarian cancer cell line caov3 by recognizing and degrading dcr3 mrna .
it has been reported that dcr3 is expressed by epithelial ovarian cancers , concentrated in ascites , and ovarian cancer with high levels of dcr3 is associated with fas - l - induced apoptosis and platinum resistance .
several clinicopathological characteristics are known to be associated with poor prognosis , including large tumor size , advanced tumor stage , poor differentiation , deep invasion , lymph node metastasis , perineural invasion , and lymphatic and vascular invasion [ 3741 ] .
a previous meta - analysis   reported that overexpression of dcr3 was closely related with some clinicopathological features , including tnm stage , grade of differentiation , lymph node metastasis , infiltration degree , and metastasis in gastrointestinal cancer .
some researchers have reported close correlations between dcr3 expression and prognosis of female reproductive cancer , but no clear evidence was provided .
our analysis suggests that overexpression of dcr3 is related to risk of female reproductive cancer , advanced tnm stage , poor differentiation , and worse lymph node metastasis .
after subgroup analysis , overexpression of dcr3 in cervical cancer , ovarian cancer , and breast cancer all had a consistent relationship with these clinicopathological parameters .
to the best of our knowledge , the present meta - analysis is the first to explore the potential relationship between dcr3 expression and female reproductive cancers .
first , we only included 12 studies ( including 1127 female reproductive cancers patients ) , in which just 3 studies ( including 290 female reproductive cancers patients ) investigated the correlation between dcr3 expression and overall survival time .
therefore , the association of dcr3 expression with overall survival time still needs to be studied in a larger number of samples .
second , there could be potential country bias in our meta - analysis , because only 1 study was performed in the usa , and the patients in the other 11 studies were chinese .
third , although we aimed to study the relationships between dcr3 expression and all female reproductive cancers , only 3 types of female reproductive cancers were recently eligible : cervical , ovarian , and breast cancer .
we will continue to study the relationship between dcr3 expression and other female reproductive cancer types , such as ovary , endometrial , choriocarcinoma , and fallopian tube cancer , and we will update our meta - analysis accordingly .
our meta - analysis indicates a positive association between the overexpression of dcr3 and carcinogenesis , deterioration , and progression of female reproductive cancers . in conclusion ,
female productive cancer risk is strongly dependent on overexpression of dcr3 , and dcr3 may be used as a biomarker to predict unfavorable cancer prognosis .
in addition , our group has previously proved that dcr3 neutralizing antibodies can suppress cell growth and induce apoptosis in glioma cells , which suggests that dcr3 could be a target in molecular therapy in cancers , including female reproductive cancers .
 backgrounddcr3 ( decoy receptor 3 ) has been proposed be involved in development and prognosis of female reproductive cancers , including cervical cancer , ovarian cancer , and breast cancer . 
 the purpose of this meta - analysis was to explore the evidence for the correlation between dcr3 and the clinicopathological characteristics , as well as the overall survival time , in female reproductive cancers.material/methodsrelevant studies were searched for in pubmed , wiley online library , web of science , science direct , cochrane central register of controlled trials , google scholar , embase , ovid , lilacs , chinese cnki , chong qing vip , wan fang , and china biology medicine disc up to 30 september 2015 . 
 data on the relationship between dcr3 expression and tnm stage , differentiation , lymph node metastasis , age , and overall survival time were extracted . 
 pooled odds ratios ( ors ) and 95% cis ( confidence intervals ) were estimated by forest plot.resultstwelve studies with 1127 patients met the inclusion criteria for this meta - analysis . 
 overexpression of dcr3 was significantly related to the risk of female reproductive cancers ( or=10.69 , 95% ci : 6.3318.05 ) , tnm stage ( or=5.51 , 95% ci : 2.8310.71 ) , differentiation ( or=4.16 , 95% ci : 2.287.60 ) , lymph node metastasis ( or=5.89 , 95% ci : 3.1610.9 ) , age ( or=0.85 , 95% ci : 0.511.44 ) , and overall survival time ( or=1.84 , 95% ci : 0.585.83 ) . 
 subgroup analyses showed that overexpression of dcr3 in cervical , ovarian , and breast cancer all had similar relationships with these clinicopathological parameters.conclusionsour meta - analysis suggests that overexpression of dcr3 may play vital roles in the tumorigenesis and deterioration of female reproductive cancers . 
 however , the relationship between dcr3 expression and prognosis needs further investigation . 