The proximal, mid, and distal esophageal cancers have different biological characteristics. Therefore, surgical and radiation treatment options are usually different. In this study, we selected the DEGs among the three types of esophageal cancers to screen the targeted molecules for the treatment of esophageal cancers. After analysis, six genes were screened to be differentially expressed in all three groups. Additionally, hundreds of DEGs specific to three comparison groups were also analyzed. These genes may serve as potential therapeutic targets for esophageal cancers.
In this study, six genes were differentially expressed among the three groups. KCNA1 and CYP3A5 were regulated by nifedipine, which is the most common kind of calcium channel blocker and is used to treat high blood pressure and angina. Especially, calcium channel blockers were recently reported to be associated with cancer . A previous study has reported that cancer cells that have DNA mismatch repair deficiency are resistant to many cytotoxic drugs. Calcium channel blockers may inhibit the pathways that cause drug-resistance . Thus, we speculated that KCNA1 and CYP3A5 might be therapeutic targets of esophageal cancer.
CA10 and REG3A were significantly correlated in the prognosis of patients with esophageal cancer. The CA10 gene encodes a protein belonging to the carbonic anhydrase family of zinc metalloenzymes. Hypoxia and acidosis are prominent features of many tumors, leading to a different metabolism from normal or healthy cells. Two of the simplest metabolic products, protons, and bicarbonate, are produced by the catalytic activity of the carbonic anhydrase . Carbonic anhydrase IX is considered as a molecular marker that may predict the prognosis of renal cancer . REG3A is a member of the REG protein family, which has been demonstrated to be involved in the development of some digestive tumors, including gastric cancer, hepatocellular carcinoma, and colorectal cancer . However, its role in esophageal cancer has not yet been reported.
For the other two genes UNC5CL and CCDC196, UNC5CL was found to be regulated by miR-337-3p and miR-512-5p. miR-337 has been reported to distinguish esophageal squamous cell carcinoma patients from healthy controls . Interestingly, a recent study reported that rs10484761 loci, located in a region of ~ 200-kb on chromosome 6p21, near UNC5CL gene, was a novel susceptible locus for esophageal squamous cell carcinoma. CCDC196 belongs to coiled-coil domain-containing proteins that are directly associated with migratory, invasive, and metastatic phenotypes of cancer cells [28–30]. The role of CCDC196 in esophageal cancer is unknown. Taken together, given the significant differential expression of the KCNA1, CYP3A5, CA10, REG3A, UNC5CL, and CCDC196 among three tumor locations, we speculate that these genes might serve as the potential molecular targets for the treatment of all proximal, mid, and distal esophageal cancers. Additionally, CA10 and REG3A might also be potential prognostic factors of esophageal cancer.
In addition to common genes found in the three groups, there were also some genes specific to each position of esophageal cancers. The distal vs. mid groups had the most specific DEGs (766), which suggested that there may exist large differences between the two positions. Mid vs. proximal groups only screened 99 specific DEGs. Interestingly, functional analysis showed that the seed genes of distal vs. mid groups (including EDN3, CGA, CCR9, and GABRA2), as well as genes in mid vs. proximal group (such as GCGR, OXTR, and MCHR2), were significantly enriched in neural functions, including neuroactive ligand-receptor interaction, transmission of nerve impulse, and neuronal system. Emerging evidence has suggested that nervous microenvironment plays a critical role in cancer progression [31–33]. Quail et al.  have reported that nervous microenvironment is an important factor in the early stage of invasion and metastasis of pancreatic cancers. Therefore, treatment targeted at neuro-microenvironment may provide a novel strategy to prevent the progression of some cancers.
Nevertheless, the role of the neuronal system in esophageal cancer has not been fully studied. We speculate that EDN3, CGA, CCR9, and GABRA2 might serve as potential targets during the treatment of distal and mid esophageal cancers. Additionally, GCGR, OXTR, and MCHR2 may be therapeutic targets of mid and proximal esophageal cancers.
In the distal vs. proximal groups, there were 314 specific DEGs, including CYP2C8 and OXGR1. CYP2C8 encodes a member of the cytochrome P450 superfamily of enzymes, which play essential roles in the metabolism of endogenous and exogenous molecules . The local expression of cytochrome P450s is essential for cancer management since these functionally associated enzymes might be involved in determining the anticancer drug sensitivity . OXGR1 belongs to the G protein-coupled receptor superfamily, and it is frequently found to be hypermethylated in hepatocellular carcinoma . A recent study revealed that overexpression of OXGR1 promoted prostate cancer development . Thus, we speculated that CYP2C8 and OXGR1 might be used as biomarkers to distinguish between distal and proximal esophageal cancers.
Although the genes screened from our analyses are promising candidate genes, we have not validated these genes through in vivo or in vitro experiments. Therefore, we will further validate and strengthen our findings by developing animal models and collecting clinical samples.
In conclusion, KCNA1, CYP3A5, CA10, REG3A, UNC5CL, and CCDC196 may serve as the potential molecular targets for the treatment of all proximal, mid, and distal esophageal cancers. CA10 and REG3A may be prognostic factors of esophageal cancer. EDN3, CGA, CCR9, and GABRA2 may serve as potential targets during the treatment of distal and mid esophageal cancers. GCGR, OXTR, and MCHR2 may be therapeutic targets of mid and proximal esophageal cancers. CYP2C8 and OXGR1 may be used as biomarkers to distinguish between distal and proximal esophageal cancers.