Protein tyrosine kinase-7 (PTK7) is a member of receptor protein tyrosine kinases (RTKs) and comprised of three domains: an extracellular immunoglobulin-like domain, a transmembrane domain, and an inert tyrosine kinase-like domain [
1]. Since the conserved catalytic residues are absent from its kinase-like domain [
2‐
4], PTK7 lacks functional catalytic tyrosine kinase activity like other RTKs, and hence is classified as a pseudokinase. Despite being a pseudokinase, PTK7 is considered as a potentially important prognostic marker for many cancers. Overexpression of PTK7 has been found in colon cancer, lung cancer, gastric cancer, acute myeloid leukemia, and intrahepatic cholangiocarcinoma [
5‐
11]. Disruption of PTK7 expression can repress cell proliferation and can promote apoptosis in colon and liver cancers [
11,
12]. More importantly, intrahepatic cholangiocarcinoma patients with low PTK7 levels had longer disease-free and overall survivals than those with high PTK7 levels [
11], suggesting it may serve as a prognostic predictor. On the other hand, PTK7 is a versatile co-receptor that can form complexes with Wnt, plexin, or vascular endothelial growth factor receptor 1 (VEGFR1) to regulate morphogenetic movement, axon guidance, cell migration, and tube formation during angiogenesis and differentiation [
13‐
17]. Notably, given that Wnt signaling plays significant roles in human cancer [
18] and that a recent study has shown that knockdown of PTK7 can inhibit Wnt/β-catenin activity [
2], it is conceivable that PTK7 may also be involved in cancer development and progression. Although dysregulation of PTK7 has been reported in some cancers, its role in tumorigenesis and oncogenic progression awaits further demonstration. Therefore, we become motivated to investigate the functions of PTK7 in esophageal squamous carcinomas in the current study.
Esophageal cancer is one of the commonly diagnosed cancers globally and is one of the leading causes of cancer-related deaths worldwide. Squamous cell carcinoma and adenocarcinoma are the two major types of esophageal cancer, each of which is associated with different risk factors. Prognosis of esophageal cancer patients is very poor, with the overall 5-year survival rate lingering below 15% in the USA [
19]. Most patients die within 1 year of diagnosis, because the disease has already progressed to advanced stages by the time when first symptoms appear. Despite advancement in diagnosis and management of esophageal cancer, its prognosis is hardly improved. However, if the cancer could be diagnosed at early stages, the 5-year survival rate would be significantly improved to about 80%. Currently, treatment of esophageal cancer is still dictated by the clinical parameters, including the TNM (tumor, node, and metastases) stages and the histological tumor characteristics. However, some reports have suggested that tumor heterogeneity is associated with prognosis [
20,
21]. Even similarly staged tumors may respond very differently to the same treatment. Therefore, it is imperative to discover new biomarkers to assist with stratification of patients for customized treatment and to minimize the unfavorable side effects or costs that are associated with the current standard chemotherapy or radiotherapy.
The goal of the current study is to investigate the role of PTK7 in the oncogenic progression of esophageal cancer. Specifically, we evaluated the expression of PTK7 in esophageal cancer by Oncomine expression analysis and validated the observation in clinical tumor samples by immunohistochemistry (IHC) staining of the PTK7 protein. We knocked down PTK7 in two esophageal squamous carcinoma cell lines and measured proliferation and apoptosis of these PTK7-deficient cells. We further characterized migration and invasion of these PTK7-knockdown cells. The current data suggest that PTK7 plays an oncogenic role in the proliferation and metastasis of esophageal squamous carcinoma cells. Importantly, PTK7 achieve its oncogenic function in human esophageal squamous cell carcinoma partially through the attenuation of apoptosis. Given the fact that the esophageal cancer biomarkers are scarce for clinical use, our ongoing work on PTK7 has significant implications in the diagnosis and treatment of this cancer.