In this study, we used several web-portal to explore the early diagnostic and prognostic value of BIRC5 in ccRCC patients by integrated bioinformatics analysis. Compared with a healthy population, the BIRC5 expression level in patients with early-stage ccRCC is significantly higher, which means that BIRC5 may be an early diagnostic biomarker for ccRCC. Moreover, BIRC5 expression is highly correlated with the ccRCC clinical and pathological stage, and BIRC5 expression is significantly increased in the higher clinical and pathological stage. We analyzed the relationship between BIRC5 expression and prognosis of ccRCC and found patients with high BIRC5 expression had a worse overall survival or disease-free survival. These results suggested that the high expression of BIRC5 prominently correlated with the prognosis and development of ccRCC, which means that BIRC5 is an important predictor of ccRCC patient prognosis.
ccRCC is a very invasive and chemoresistant disease which is often treated by surgical resection . ccRCC can be cured by surgery when diagnosed at an early stage. However, it’s usually asymptomatic at early stage and hard to diagnose in the early days [3, 4]. Unfortunately, ccRCC has high rates of local invasion and metastasis  and there are no effective therapies to reduce the risk of recurrence, progression or death. Therefore, there is an urgent need for reliable biomarkers of ccRCC, enabling early diagnosis, prognosis, and monitoring of potential relapse of the disease.
However, there is no simple and rapid method to early detect ccRCC. For example, as a gold standard for ccRCC diagnosis, renal biopsy has a high sensitivity of diagnosis with a low complication rate of less than 5% ,however due to the asymptomatic of ccRCC at an early stage, it cannot diagnose at the early days through renal biopsy. What’s more, M. SadatKhonsari et al found that patients with suspicious renal masses cannot be precluded from being diagnosed with malignancies although, with an unsuspicious histology in CT-guided renal tumor biopsy and almost 30% of these patients, further diagnostic or therapeutic workup demonstrated a cancer diagnosis . Previous several studies in other cancer types already showed that survivin can also be measured in the serum using a human surviving enzyme-linked immunosorbent assay (ELISA)[14, 15, 16, 17, 18] which makes it a noninvasive method for detecting ccRCC. In our study, the BIRC5 expression level in patients with early-stage ccRCC is significantly higher than in a healthy population. So we assume survivin may be an early diagnostic biomarker for ccRCC, but it’s sensitivity and specificity need to be clear by further clinical trials.
Previous studies have suggested increased BIRC5 expression contributes to the negative outcomes of various cancers, such as breast, lung, colorectal, prostate, and ovarian cancer . CAO et al  found that high BIRC5 expression is related to tumor progression and poor prognosis of lung adenocarcinoma. Narimani M et al  found that knock-down of BIRC5 induces apoptosis in acute myelocytic leukemia (AML). What’s more, two meta-analyses suggested that high BIRC5 expression was associated with poor prognosis and a more advanced pathological stage of renal cell carcinoma [21, 22]. In this study, we certify that high BIRC5 expression is associated with worse prognosis in ccRCC patients. Our findings are consistent with existing investigations. Therefore, we hypothesis that BIRC5 is a potential biomarker for progression and therapeutic target of ccRCC patients.
BIRC5 is a mitotic spindle checkpoint gene and is located near the telomeric end of chromosome 17 . It plan an important role in the regulation of mitosis and apoptosis of cell, also involved in pathological processes . Its encoded protein, survivin, has two phosphorylation sites on its different domains (Thr34 and Thr117) which determine its bifunctional molecule effect on apoptosis and cell proliferation. Thr34 is a site on the regulation of cell apoptosis when the Thr117 is involved in proliferation and cell cycle . Previous studies demonstrate that BIRC5 is a key target involved in a variety of cancer cell signaling pathways and the up-regulation of BIRC5 may play a role in the following several mechanisms. First, it can antagonize caspase-dependent apoptosis and activate P53 and its downstream target P21 to achieve the purpose of stalling cell cycle progression . Second, BIRC5 facilitates the invasion and migration of tumor cells mediated through the PI3K/AKT pathway  or the TGF-β pathway . Another, it can regulate tumor cell proliferation mediated by theβ-catenin pathway . These results may explain BIRC5 was mainly involved in the regulation of cell cycle and apoptosis. Meanwhile, our study indicates that the high expression of BIRC5 promoted the development of ccRCC which may be through regulating the cell cycle signaling pathway.
The main limitation of our study is that our study was conducted using data from public databases that were not verified in prospective clinical trials. These findings need to be validated in prospective clinical trials. Moreover, as a potential biomarker for early diagnosis, the specific concentration of survivin to diagnose ccRCC needs to be further determined by clinical trials, also its sensitivity and specificity need to be clear. Also, the mechanisms through which BIRC5 promotes the progression of ccRCC require further investigation and the functions of the BIRC5 that impact the development of ccRCC need to be investigated further through in vivo and in vitro experiments.
In conclusion, for ccRCC, BIRC5 may serve as a promising early diagnostic or prognostic predictor and therapeutic target. However further investigations are necessary to confirm the findings of our study.