High endothelin-converting enzyme-1 expression independently predicts poor survival of patients with esophageal squamous cell carcinoma

Introduction

Esophageal cancer, the eighth most common cancer causing more than 400,000 deaths per year in the world, is especially popular in Africa and East Asia.¹ In Taiwan, esophageal cancer, of which esophageal squamous cell carcinoma (ESCC) is the major subtype, is the fifth leading cause of cancer-induced deaths in males.² At the time of diagnosis, most patients have locally advanced, unresectable, or metastatic disease status (stage II–IV). Overall, 60% of patients could receive only palliative therapy.³ Even though some patients could receive curative surgery, their 5-year survival rates are usually less than 40%⁴ due to high recurrence rate (around 40%–60%).^5,6 Although neoadjuvant chemoradiotherapy (CRT) plus surgery provides better patient survival than surgery alone in patients with locally advanced esophageal cancer, these patients suffer from more postoperative mortalities.⁷ In order to provide adjuvant therapy besides surgery to patients with poor prognosis or high recurrence, we need biomarkers to identify this high-risk group. However, no such biomarkers are available now.

The endothelin (ET) family includes three isoforms of 21 amino acid peptides, ET-1, ET-2, and ET-3.⁸ All ETs are synthesized as inactive forms and converted to active ETs through serial processing. ET-converting enzyme-1 (ECE-1), which has four isoforms, catalyzes the conversion of pro-ETs into active ETs,⁹ which then bind to G protein–coupled receptors ET-A receptor (ET_AR) and ET-B receptor (ET_BR) with variable affinities.^10,11 Activation of the ET axis has great influence in many cancers.¹² Mounting evidence has shown that ET-1/ET_AR interaction induces phosphorylation of endothelial growth factor receptor,¹³ inhibits apoptosis,¹⁴ and promotes angiogenesis¹⁵ and proliferation¹⁶ of tumor cells. Moreover, preclinical data have supported the therapeutic potential of ET_AR antagonists in gynecological, urological, and breast cancers, which further proves the importance of ET axis in cancer progression.¹⁷

The role of ET axis in human ESCC has just been elucidated. Human ESCC, which has ET_AR and ET_BR on their surface,^18,19 expressed more ET-1 compared to adjacent normal tissues.²⁰ Blockade of ET signaling pathway by ET_AR/ET_BR antagonist could inhibit ESCC growth¹⁸ and reduce invasive ability of ESCC cells through downregulating cathepsin B.²⁰ Moreover,...