Clinicopathological and functional implications of the inhibitor of apoptosis proteins survivin and XIAP in esophageal cancer

Abstract

Abstract. Based on their overexpression and important roles in progression and therapy-resistance in malignant diseases, the inhibitor of apoptosis protein family (IAP) members, survivin and X-linked inhibitor of apoptosis protein (XIAP), represent attractive candidates for targeted therapy. The present study investigated the prognostic and biological relevance of survivin and XIAP in esophageal squamous-cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Survivin and XIAP expression was analyzed by immunohistochemistry using tissue microarrays containing 120 ESCC and 90 EAC samples as well as the corresponding non-neoplastic esophageal mucosa samples. IAP expression levels were then correlated to clinicopathological parameters and overall survival to identify any associations. In addition, esophageal cancer cell lines were treated with the survivin inhibitor YM155, and the XIAP inhibitors Birinapant and GDC-0152 in vitro. Survivin and XIAP expression were significantly increased in EAC and ESCC when compared with tumor-adjacent mucosa. In patients with ESCC XIAP expression was associated with female gender and advanced tumor stages, and nuclear survivin expression was associated with poor grading. High XIAP expression was identified as an independent negative prognostic marker in ESCC. By contrast, XIAP inhibitors did not affect cancer cell viability in vitro, and the small molecule survivin inhibitor YM155 significantly reduced cell viability and proliferation in esophageal cancer cell lines. Western blot analysis revealed a dose dependent decrease of survivin accompanied by an increased poly (adenosine diphosphate-ribose) polymerase cleavage following YM155 treatment. These findings underline the potential role of survivin and XIAP in the oncogenesis of esophageal cancer and provide a rationale for future clinical studies investigating the therapeutic efficacy of IAP directed therapies in patients with esophageal cancer.

Elevated X-linked inhibitor of apoptosis protein (XIAP) expression uncovers detrimental prognosis in subgroups of neoadjuvant treated and T-cell rich esophageal adenocarcinoma

“…Other studies previously reported a survival benefit for patients with lower expression of XIAP in comparison with patients expressing high levels of XIAP in esophageal squamous cell carcinoma (ESCC) but were not able to reveal a difference in OS in esophageal adenocarcinoma [23]. In contrast to the current study, only a relatively small group of patients was examined in which, due to the limited number of patients, sufficient subgroup analyses may not lead to significant results.…”

Prognostic Value of XIAP Level in Patients with Various Cancers: A Systematic Review and Meta-Analysis

“…All studies were retrospective design and the sample size ranged from 29 to 1103. The patients were diagnosed with various solid carcinomas, among which digestive tumors accounted for the most type, particularly gastric cancer (n=4) 25-28, colorectal cancer (n=3) 29-31, HCC (n=5) 12, 17, 32-34, esophageal cancer (n=2) 11, 35, cholangiocarcinoma (n=2) 36, 37 and pancreatic cancer (n=1) 38. And the remaining studies included breast cancer (n=4) 16, 18, 19, 39, NSCLC (n=2) 13, 40, head and neck cancer (HNC) (n=4) 41-44, thyroid cancer (n=4) 15, 45-47, prostate cancer (n=2) 14, 48, renal cancer (n=2) 49, 50 and other tumor types (n=5) listing as: sebaceous gland carcinoma, glioblastomas, ovarian cancer, bladder cancer and malignant mesothelioma 51-55.…”

“…It was slowly emerging as a potential therapeutic target for cancer management. Recently, many scholars have carried out series of studies to explore the expression of XIAP and its association with patient outcomes in different types of tumors, such as hepatocellular carcinoma (HCC), breast cancer, non-small cell lung cancer (NSCLC), esophageal cancer, thyroid cancer, prostate cancer 11-16. However, these results remain controversial.…”

Prognostic significance of X-linked inhibitor of apoptosis protein in patients with gastrointestinal tract cancers

“…The rest studies were further evaluated in full text and 31 were excluded due to unrelated, lacking enough data or other reasons. Eventually, 12 studies [ 12 , 14 – 22 , 24 , 25 ] met the inclusion criteria and were included. The study selection process was shown in Figure 1 .…”

“…Dizdar et al [ 25 ] showed that XIAP could be a prognostic marker in ESCC but not in EAC. Their findings were consistent with our subgroup analyses results.…”