Predictive Value of E-cadherin, β-catenin and SOX4 in Recurrence and/or Progression of Non-muscle Invasive Urinary Bladder Transitional Cell Carcinoma. A Retrospective Study

Bladder cancer (BC) is one of the most common genitourinary malignancies worldwide. [1]

The incidence of BC increases with age, with a high incidence among those 50-70 years old. The incidence of BC in males is three- to four-times higher than that in females [2]. The etiology and pathogenesis of BC are complex, with both internal genetic factors and external environmental factors. Smoking and occupational exposure to aromatic amine chemicals (such as aniline, 2-aminobiphenyl, 2-naphthalene, 1-naphthalamines etc.) are the two major risk factors for BC [3].

At present, some studies suggest that the abnormal function of intercellular adhesion molecules is highly correlated with the invasion of surrounding tissues and distant organ metastasis of BC [4].

BC is typically grouped into two main pathological classes non-muscular invasive bladder cancer (NMIBC) which is further sub classified according to histological grade (low or high), and muscular invasive bladder cancer (MIBC) according to the European Association of Urology (EAU) guidelines. BC can also be divided into several types-transitional cell carcinoma (TCC), squamous epithelial carcinoma, and adenocarcinoma-among which over 90% are TCC [5].

While histological and pathological grading and staging systems exist for some time, recent advances in genomic sequencing have lent insight into molecular characterizations that stratify patients into various subtypes based on genetic markers, such as amplifications, mutations and deletions [6].

The current standard treatment of patients with non-muscle-invasive bladder cancer (NMIBC) is complete removal of the visible tumor burden by transurethral resection (TUR), and the prognosis of such patients is generally favorable, achieving 5-year survival rates greater than 80% [7].

However, the high probability of intravesical recurrence in patients undergoing TUR has been reported to range between 30% and 80% in patients with NMIBC [7-8]. Intensive efforts, therefore, have been made to identify factors precisely predicting the clinical course of NMIBC following TUR, which are of great utility in planning both postoperative adjuvant therapy and follow-up schedule in an individual patient.

Of patients with BC 50% to 55% present with Ta tumors, for which recurrence is the main clinical issue, occurring in up to 80% [9-10].

However, for the 20% to 25% of patients presenting with T1 tumors, progression is the main clinical concern, occurring in up to 45% [9-10]. Progression to or presentation with muscle invasive disease (stage T2-4) represents the critical step in the disease course of bladder cancer, Necessitating more radical and aggressive therapies, including surgery, chemotherapy or radiotherapy, and carrying a 5-year survival rate of only 27% to 50% [10].

These aggressive therapies represent relatively crude approaches with significant morbidity and mortality [11].

Cadherins are the main mediators of cell-cell adhesion in epithelial tissues; E-cadherin is an important transmembrane glycoprotein of epithelial cell adhesion. It is also an inhibitor of tumor invasion and metastasis. It plays an important role in maintaining cell morphology, cell movement, and adhesion function [12].

E-cadherin needs β-catenin to mediate and participate in its physiological function. β-catenin is an E-cadherin-related protein. The intracellular domain of E-cadherin is connected with β-catenin to form a β-catenin/E-cadherin complex, which is transported to the cell membrane through the cytoplasm and inserted into the cell membrane to maintain the polarity and stability of epithelial cells [13].

In the process of tumorigenesis, the abnormality of β-catenin affects the stability of the β-catenin/E-cadherin complex, which leads to a decrease in cell junction density and the loss of cell contact inhibition function. In the development of tumors, it manifests as invasion and metastasis [13-14].

Furthermore, the abnormal expression of Cadherins (cadherin switching) has been shown to promote a more invasive and malignant phenotype of cancer, and possibly even acts as the principal mediator of invasion and metastasis in BC [15].

SOX (SRY-related HMG-box) family of transcription factors involved In organogenesis of various organs. One of the candidate is located at the chromosome 6p22 locus is Sox4 [16],

SOX4 gene expression is upregulated in many cancer types, and it's increase activity contributes to cellular transformation, cell survival, and metastasis [17].

SOX family of proteins are found in all metazoans, and high expression of SOX4 has been used to recognize the presence of CSCs. This approach has been applied in some studies of TCC [18].

The cancer stem cells (CSCs) hypothesis is based on the observation of many cancers, including bladder cancer, are driven by a subpopulation of tumor-initiating cells (popularly known as CSCs) and promote tumor growth. In addition, CSCs are resistant to chemotherapy and radiation treatments, which potentially explains the limitations of curing human malignancies [19].

Down-regulation of SOX4 led to mesenchymal-to-epithelial transition (MET) and inhibition of cell migration. Of note, knockdown of SOX4 reduced sphere formation, aldehyde-dehydrogenase-high (ALDH) cell population and potential of tumor formation. Furthermore, immunohistochemistry (IHC) analysis of human bladder tumor tissue microarrays (TMAs) indicated that high SOX4 expression correlated with advanced tumor stages and poorer survival of urinary bladder cancer patients. Providing the first evidence, that SOX4 may act as an oncogene [20].

In this study, we hope to develop the correlation regarding the alternation in the expression of E-cadherin, β-catenin and Sox4 in determining the recurrence, progression and up staging and their prognostic value in NMIBC.