MiR-338-5p enhances the radiosensitivity of esophageal squamous cell carcinoma by inducing apoptosis through targeting survivin.

Radioresistance is a challenge in the treatment of esophageal squamous cell carcinoma (ESCC). MicroRNAs (miRNAs) are known to play an important role in the functional modification of cancer cells and recent studies have reported miRNA-mediated radiotherapy resistance. However, further research is necessary to reveal the regulation mechanisms, and treatment strategies using miRNA are yet to be established for ESCC. We compared the miRNA expression profiles of ESCC parental (TE-4) and acquired radioresistance (TE-4R) cell lines using a miRNA microarray and qRT-PCR. Our data showed that miR-338-5p, one of the target miRNA biomarkers, was significantly downregulated in TE-4R. Ectopic overexpression of miR-338-5p induced apoptosis and sensitivity to radiation treatment by interfering with survivin, which is a known inhibitor of apoptosis. Overexpression of survivin reversed miR-338-5p-induced apoptosis. Tumor xenograft experiments indicated that therapeutic delivery of the miR-338-5p mimics via direct injection into tumor mass increased sensitivity to radiation therapy. In conclusion, our findings suggest that miR-338-5p is a potential radiosensitizer and may be a therapeutic biomarker for radioresistant in ESCC.

PTK7 regulates radioresistance through nuclear factor-kappa B in esophageal squamous cell carcinoma.

Tumor radioresistance is a major reason for decreased efficiency of cancer radiation therapy. Although a number of factors involved in radioresistance have been identified, the molecular mechanisms underlying radioresistance of esophageal squamous cell carcinoma (ESCC) have not been elucidated. In this study, we investigated the role of oncogenic protein tyrosine kinase 7 (PTK7) in the resistance of ESCC to radiation therapy. ESCC cell lines with high PTK7 expression were more refractive to radiation than those with low PTK7 levels. In radioresistant ESCC cells, PTK7 knockdown by specific siRNAs decreased the survival of irradiated cells and increased radiation-induced apoptosis, while in radiosensitive ESCC cells, PTK7 overexpression promoted cell survival and inhibited radiation-induced apoptosis. We hypothesized that PTK7 could regulate the activation of transcription factor NF-kB known for its role in cancer radioresistance. Our results indicated that the inhibition of PTK7 suppressed nuclear translocation of NF-kB subunit p65 induced by radiation, suggesting relevance of PTK7 expression with NF-kB activation in radioresistant ESCC. Furthermore, the levels of inhibitor of apoptosis proteins (IAPs), XIAP, and survivin, encoded by NF-kB-regulated genes, were induced in irradiated radioresistant cells but not in radiosensitive cells, while PTK7 knockdown downregulated IAP expression. Our findings revealed a novel mechanism underlying radioresistance in ESCC, which is associated with PTK7 and NF-kB-dependent apoptosis. These results suggest that the manipulation of PTK7 expression can be instrumental in enhancing ESCC response to radiotherapy. This study demonstrates that PTK7 plays a significant role in ESCC radioresistance via the NF-kB pathway.

Cetuximab inhibits cisplatin-induced activation of EGFR signaling in esophageal squamous cell carcinoma.

A malignant esophageal cancer, squamous cell carcinoma is one of the most prevalent cancers. Despite the use of present surgical techniques combined with various treatment modalities, the overall 5-year survival rate remains at 15-34%. Epidermal growth factor receptor (EGFR) is the most well studied receptor in various cancers and EGFR overexpression is detected in 40% of esophageal squamous cell carcinomas (ESCCs) and ESCC cell lines. To examine the EGFR antibody combination effect, we used treatment with cisplatin and cetuximab in ESCC cell lines, TE-4 and TE-8. Combination of cetuximab and cisplatin resulted in a growth inhibition only in the EGFR overexpressed TE-8 cell line. Furthermore, we confirmed that cisplatin-induced EGFR activation was inhibited by cetuximab in TE-8 but not in TE-4 cells. Our data suggest that cetuximab combined with cisplatin exerts antitumorigenic effects in vitro and in vivo via suppression of EGF signaling, which can be applied toward targeted ESCC treatments.

Protein tyrosine kinase 7 plays a tumor suppressor role by inhibiting ERK and AKT phosphorylation in lung cancer.

Protein tyrosine kinase 7 (PTK7) is a catalytically inactive receptor tyrosine kinase that is also known as colon carcinoma kinase-4 (CCK-4). Recent reports have shown that PTK7 plays an important role in carcinogenesis, and it is known to be upregulated in gastric, colon and esophageal cancer, as well as in liposarcoma. However, the role of PTK7 in lung cancer has not been investigated. The aim of the present study was to investigate the expression levels and the role of PTK7 in lung cancer. We found that PTK7 expression was downregulated at the mRNA as well as protein levels in human lung squamous cell carcinoma (LSCC). Upon investigation of the functional role of PTK7 in LSCC, we found that overexpression of PTK7 in LSCC cells resulted in inhibition of cell proliferation, invasion and migration. Furthermore, we confirmed that these phenotypic changes are associated with the inactivation of AKT and ERK. Our findings suggest that PTK7 has different oncogenic roles in organs and target tumors.

Integrin alpha 6: a novel therapeutic target in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC), the most common subtype of esophageal cancer in East Asian countries, is a devastating disease characterized by distinctly high incidence and mortality rates. Our previous expression profile analysis showed that integrin alpha 6 (ITGA6) is highly expressed in ESCC tissues. To validate cell surface expression of ITGA6 as a novel target in ESCC, we investigated ITGA6 expression in tumor tissue samples and cell lines of ESCC and found that ITGA6 was upregulated in these cells. In vitro knockdown of ITGA6 in ESCC cells resulted in inhibition of cell proliferation, invasion and colony formation. In addition, we demonstrated that ITGA6 associates with integrin beta 4 (ITGB4), and that this heterodimer complex is upregulated in both ESCC tissues and cell lines. Moreover, our biodistribution results in an ESCC xenograft model indicated that ITGA6 is a possible target for antibody-related diagnostic and therapeutic modalities in ESCC. Thus, our findings suggest that ITGA6 plays an important role in tumorigenesis in ESCC and represents a potential therapeutic target in the treatment of ESCC.