Urologic Oncology: Seminars and Original Investigations
Original articleLow expression of TMEM67 is a critical predictor of poor prognosis in human urothelial carcinoma of the bladder
Introduction
Urothelial carcinoma of the bladder (UCB) is the most common urothelial malignancies which accounts for 3.3% of newly diagnosed cancer cases and 2.1% of cancer deaths in the world [1]. Overall, 70% of bladder tumors present as noninvasive urothelial carcinoma, and the remainder present as muscle-invasive disease [2]. So, an accurate biomarker or prognosis factor is essential for efficient management of UCB.
TMEM67, also named Meckelin, is a transmembrane protein encoded by TMEM67/MKS3, localizing to the primary cilium and the plasma membrane [3], [4], [5]. Genotype-phenotype analyses indicated that recessive mutations at the TMEM67 locus were associated with dysfunction of primary cilia [4], [5], [6]. Primary cilia are ubiquitously present in cell surface organelles with essential functions in cellular proliferation, differentiation and development. Emerging evidences suggest that in many cancers [7], [8], [9], [10], primary cilia are markedly decreased or absent. To date, however, abnormalities in TMEM67 and their influence to UCB have not been declared.
In this study, we explored the expression status of TMEM67 in UCB and evaluated its possible biogenic role as a prognostic biomarker for patients with UCB.
Section snippets
Patients and tumor specimens
A total of 134 tissues (54 UCB and noncancerous tissues by radical cystectomy, 26 UCB tissues by TURBT) were obtained from patients with UCB, who were diagnosed by pathological examination at the Second Hospital of Tianjin Medical University from January 2005 to October 2013, and 54 noncancerous tissues were collected outside 3 cm adjacent to carcinoma tissues as control at the same time. No patient was preoperatively treated with either radiotherapy or chemotherapy and postoperatively treated
Low expression of TMEM67 in UCB tissues
To evaluate the biogenic role of TMEM67 in UCB, we examined the expression of TMEM67 in noncancerous tissues and cancer tissues by qRT-PCR, IHC, and Western blot analysis. The results showed that the expression of TMEM67 mRNA was significantly lower in UCB tissues compared to those in noncancerous tissues (Fig. 1A, P = 0.0161). As shown in Fig. 1B, the TMEM67 protein was differentially low expressed in 11 UCB samples compared to corresponding adjacent noncancerous tissues. IHC staining showed
Discussion
UCB is genetically heterogeneous [11], with frequent alterations in genes regulating chromatin state, cell cycle, and receptor kinase signaling [12], [13], [14], [15] and it is a cancer with high recurrent rate and the 5-year overall survival is still unsatisfactory for advanced disease in spite of the introduction of adjuvant chemotherapy [16]. Current patient prognosis is mainly based on TNM. The high recurrence rate requires close surveillance with cystoscopy that is an invasive test, so an
Conclusions
This study data showed that TMEM67 was significantly low expressed in UCB tissues. Low expression of TMEM67 in UCB is strongly relevance with tumor stage, grade and lymph node metastasis. TMEM67 was confirmed as a prognostic biomarker in UCB by Kaplan-Meier survival and Cox regression analysis. In combination with other biomarkers of UCB, TMEM67 might be valuable for providing potential targets for new therapeutic approaches for patients with UCB.
Acknowledgment
This work was supported by National Natural Science Foundation of China (No. 81400686), Tianjin Natural Science Foundation (No. 13JCQNJC11500).
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