Abstract
Clear cell renal cell carcinoma (ccRCC) is the most frequent and aggressive subtype of renal carcinoma. So far, the basis of its oncogenesis remains unclear resulting in a deficiency of usable and reliable biomarkers for its clinical management. Previously, we showed that nuclear expression of the signal transducer and activator of transcription 3 (STAT3), phosphorylated at its serine 727 (pS727), was inversely proportional to the overall survival of ccRCC patients. Therefore, in the present study, we validated the value of pS727-STAT3 as a clinically relevant biomarker in ccRCC. This work is a retrospective study on 82 ccRCC patients treated with nephrectomy and followed-up for 10 years. Immunohistochemical expression of pS727-STAT3 was analyzed on a tissue microarray and nuclear and cytosolic levels were correlated with clinical outcome of patients. Our results showed that pS727-STAT3 levels, whether in the nucleus (p = 0.002; 95% CI 1.004–1.026) or the cytosol (p = 0.040; 95% CI 1.003–1.042), significantly correlate with patients’ survival in an independent-manner of clinicopathological features (Fuhrman grade, risk group, and tumor size). Moreover, we report that patients with high pS727-STAT3 levels who undergone adjuvant therapy exhibited a significant stabilization of the disease (~ 20 months), indicating that pS727-STAT3 can pinpoint a subset of patients susceptible to respond well to treatment. In summary, we demonstrated that high pS727-STAT3 levels (regardless of their cellular location) correlate with low overall survival of ccRCC patients, and we suggested the use of pS727-STAT3 as a prognostic biomarker to select patients for adjuvant treatment to increase their survival.
Highlights
Clear cell renal cell carcinoma is the most frequent and aggressive subtype of renal carcinoma
Multiple risk factors have been associated with the development of Clear cell renal cell carcinoma (ccRCC)17, to date, the molecular mechanisms behind its etiology are not completely understood which leads to a lack of effective biomarkers clinically usable to predict disease progression or to select patients for particular therapies
Over the past years, it has been extensively confirmed that abnormal activation of signal transducer and activator of transcription 3 (STAT3)—either by Y705 or serine 727 (S727) phosphorylation—is a key event that contributes to oncogenesis in several tumors other than ccRCC13
Summary
Clear cell renal cell carcinoma (ccRCC) is the most frequent and aggressive subtype of renal carcinoma. Numerous and extensive studies on the genetic and biochemical features of ccRCC have been performed, there are few usable markers only related to treatment outcome[11] This scenario poses the urgent need to identify specific biomarkers that can be used for early diagnosis, prognosis and to develop treatment strategies for all ccRCC patients. In this context, previous studies from our group brought to light the role of the signal transducer and activator of transcription 3 (STAT3) in ccRCC by demonstrating that its activation resulted from the overexpression of the human hepatitis A virus cellular receptor 1 (hHAVCR1), known as kidney injury molecule 1 (KIM1)[12]. These patients allowed the evaluation of the pS727-STAT3 potential to discriminate between those with different responses to adjuvant therapy
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