Review article
The role of STAT3 protein as a prognostic factor in the clear cell renal carcinoma. Systematic reviewValor de la proteína STAT3 como factor pronóstico en el carcinoma renal de célula clara. Revisión sistemática☆

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Abstract

Context and objective

There have been significant advances in the knowledge of renal carcinogenesis in the last years. Nowadays, renal tumours are classified according to their genetic profile and specific treatments based on the identification of therapeutic targets have also been developed. However, no prognostic markers have yet been identified. The aim of this review is to analyze literature that has evaluated the expression of the STAT3 protein as a molecular marker in clear cell renal carcinoma (ccRCC).

Evidence acquisition

In January 2018 a systematic review was conducted in Pubmed, Cochrane library and Sciencedirect databases, from papers published from 1990. Search terms were “renal cell carcinoma” and “STAT3” or “STAT-3” and prognostic factor. Following the principles of the PRISMA declaration and the PICO selection strategy, original articles with series of patients diagnosed with localized or metastatic ccRCC, and where the activity of STAT3 is analyzed as a prognostic marker, were selected. A total of 132 publications were identified, of which 10 were finally revised, for they met the inclusion criteria.

Evidence synthesis

STAT3 activation (phosphorylation) through Ser727 is important during ccRCC development and progression. PSTAT3 expression seems to be a prognostic marker and an antiangiogenic-resistance marker in metastatic patients. There is little evidence as prognostic marker in patients with localized disease.

Conclusions

STAT3 (Ser 727) expression in the nucleus of the ccRCC cells can be a prognostic marker and an antiangiogenic-resistance marker. Current scientific evidence is limited and more studies are needed to demonstrate its usefulness.

Resumen

Contexto y objetivo

En los últimos años se han producido avances significativos en el conocimiento de la carcinogénesis renal. Hoy en día los tumores renales se clasifican en función de su perfil genético, y además se han desarrollado tratamientos específicos basados en la identificación de dianas terapéuticas. Sin embargo, todavía no se han identificado marcadores pronósticos. El objetivo de esta revisión es analizar la literatura que ha evaluado la expresión de la proteína STAT3 como marcador molecular en el carcinoma renal de célula clara (ccRCC).

Adquisición de evidencia

En enero de 2018 se realizó una búsqueda sistemática de la literatura en Pubmed, Cochrane Library y Sciencedirect de las publicaciones realizadas desde 1990. Los términos de búsqueda fueron renal cell carcinoma and STAT3 or STAT-3 and prognostic factor. Se siguieron los principios de la declaración PRISMA y la estrategia de selección PICO, seleccionándose los artículos originales con series de pacientes diagnosticados de ccRCC localizado o metastásico, donde se analiza la actividad de STAT3 como marcador pronóstico. Se identificaron 132 publicaciones de las que finalmente se han revisado 10 por cumplir los criterios de inclusión.

Síntesis de evidencia

La activación (fosforilación) de STAT3 (pSTAT3) en el residuo Ser727 es importante en el desarrollo y progresión de ccRCC. La expresión de pSTAT3 parece ser un marcador pronóstico y predictor de resistencia a algunos tratamientos en pacientes con enfermedad diseminada. Existe poca evidencia de su utilidad como un marcador pronóstico en pacientes con enfermedad localizada.

Conclusiones

La expresión de pSTAT3(Ser727) en el núcleo de las células del ccRCC puede ser un marcador pronóstico y de respuesta al tratamiento en pacientes con ccRCC. La evidencia científica actual es limitada y son necesarios más estudios que demuestren su utilidad.

Introduction

Renal carcinoma is the third most frequent urologic neoplasm, with the clear cell subtype (ccRCC) being the most common. This type of tumour is characterized by the absence of signs and symptoms in early stages of the disease. As a consequence, up to 80% of them are diagnosed incidentally from imaging tests requested for other reasons. Despite this, up to 20% of cases can be diagnosed in advanced stages, with mortality rates of 95% at 5 years.1

For years, several research groups have sought for markers with diagnostic value that allow early detection of ccRCC. Other groups also look for markers with prognostic value once the disease is diagnosed. These studies have been aimed at analysing various factors such as demographic characteristics, risk factors and possible markers detected in biological samples or directly from the tumour itself.2

The classic molecular pathways involved in renal carcinogenesis and mainly studied are the Mammalian Target of Rapamycin (mTOR) and the signalling pathway of Hypoxia-Inducible Factor-1-Von Hippel Lindau. In this line, in 2004 our group showed that the gene that codes for the hepatitis A virus receptor protein was overexpressed in the ccRCC.3 This protein was later described in rats and defined as Kidney Injury Molecule 1 (KIM1), showing its overexpression in kidneys subjected to ischaemia and intoxication by folic acid. The gene encoding the hepatitis A virus/KIM1 receptor protein is not expressed in healthy renal tissue. However, its overexpression has been seen in proximal convoluted tubule cell carcinomas (ccRCC and papillary carcinomas) as well as a significant correlation with the Fuhrman grading of these tumours. Activation of the gp130/STAT3 pathway (phosphorylated STAT3 or pSTAT3) is regulated by KIM1, with greater levels in high-grade tumours and related to worse prognoses.4, 5, 6

The Signal Transducer and Activator of Transcription (STAT) protein family consists of 7 subtypes. All of them play two roles: transduction of signals in the cytoplasm and transcription of signals to the nucleus. The activation of this family of proteins is regulated by proinflammatory mediators (cytokines and chemokines). In the case of the activation of STAT3, the most relevant is interleukin-6. This activation is carried out by phosphorylation of 2 residues: tyrosine 705 (Tyr705) and serine 727 (Ser727), in response to cytokines. The phosphorylation of STAT3 allows its translocation to the nucleus, where it plays a crucial role in the transcription pathways required for carcinogenesis, such as regulation of cell survival, cell proliferation, angiogenesis and tumour-induced immunosuppression functions. It has also been shown that there is an aberrant activation of STAT3 in breast, prostate, ovarian neoplasms, in multiple myelomas and in neoplasms of head and neck. Persistent activation of STAT3 associated with the feedback mechanism of cytokines and other inflammatory mediators, has been well documented in multiple myeloma. This has been the first direct evidence of the relationship between persistent activation of STAT3 and human carcinomas.7, 8, 9, 10, 11, 12

Currently, scientific evidence suggests that the value of STAT3 protein expression in renal tumours is not the same in all subtypes. Its marker value seems to be demonstrated in the neoplasms derived from the proximal convoluted tubule. In 2009, a review was published analysing the activity of pSTAT3 (phosphorylated at residue Tyr705) in patients with various types of renal neoplasms (42 clear cell carcinoma, 24 chromophobe, 7 papillary, 15 oncocytoma and 7 urothelial carcinoma). The study concluded that there is greater activity of pSTAT3 in neoplasms derived from the proximal convoluted tubule and, interestingly, also found an overexpression in neoplasms of urothelial origin.13

The objective of this review was to analyze the scientific evidence on the STAT3 protein as a prognostic marker in clear cell renal carcinoma.

Section snippets

Evidence acquisition

In January 2018, a systematic search was carried out in the databases (PubMed, Cochrane Library and ScienceDirect). We selected publications in English and Spanish, from January 1, 1990, following the principles of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) declaration. The search was performed independently by 2 urologists (E.T. and D.L.). The terms used in the research were: renal cell carcinoma and STAT3 or STAT-3 and prognostic factor. According to the

Evidence summary

STAT3 activation depends on the phosphorylation of its 2 residues (Ser727 and Tyr705). In 2014 the activity of pSTAT3 was analyzed by phosphorylation in different residues, in ccRCC cell cultures and subsequently, the results were confirmed in a series of 98 patients with ccRCC (88% with localized disease and 12% metastatic). The results showed that the activation of pSTAT3 at Ser727 residue is an independent prognostic factor of survival, while phosphorylation at the Tyr705 residue is not.

Discussion

Unlike the non-neoplastic cells of the same kidney, ccRCC tumour cells overexpress the STAT3 protein. However, in order to evaluate the real activity of this protein, it is necessary to quantify its activity in the nucleus, where it participates in the carcinogenesis and progression of the disease. In 2002, Horiguchi et al. compared the expression of STAT3 in the cytoplasm and in the nucleus, observing that the global expression of the protein was not related to its activation. However, its

Conclusions

The activity of the phosphorylated STAT3 protein (pSTAT3) in the nucleus of tumour cells plays an important role in the oncogenesis of the ccRCC.

There is no sufficient evidence to consider pSTAT3 a prognostic marker in patients with non-disseminated ccRCC.

In patients with metastatic disease, its expression seems to be useful as a prognostic marker and as a predictor of response to some treatments.

More scientific evidence is required in order to consider the expression of nuclear pSTAT3 a

Conflicts of interest

The authors declare that they have no conflicts of interest.

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☆

Please cite this article as: Lorente D, Trilla E, Meseguer A, Arevalo J, Nemours S, Planas J, et al. Valor de la proteína STAT3 como factor pronóstico en el carcinoma renal de célula clara. Revisión sistemática. Actas Urol Esp. 2019;43:118–123.

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