The expression of HOXC genes is varying across various cancer types. It has been reported that HOXC genes were up-regulated in some types of cancers included colorectal (12), gastric (13), and lung (14). Some reports showed their down-regulation in a different type of Larynx squamous cell carcinoma (7). This difference in the expression among various cancers displays that these genes can play either a tumor-suppressive or oncogenic function, depending on the cancer's type (5). According to our findings HOXD10 was up-regulated in gastric cancer and it was concerned as an oncogenic gene. We showed that HOXC13 has a significant correlation with both distant metastasis and perineural invasion. Similarly, de Barros e Lima Bueno et al. (7) demonstrated that HOXD10 leads to enhance cell invasion and migration, inhibition of apoptosis, and decrease of cell survival. Metastasis is a crucial factor influencing gastric tumor prognosis and development. Guo et al. (13) further detected the efficacy of HOXC10 on gastric tumor metastasis via migration and invasion tests, demonstrating that this gene could promote gastric tumor metastasis. All together our work exhibited an important function of HOXC10 in the metastasis and proliferation of gastric tumor. It seems that HOXC10 regulates this biological progress via MAPK signaling (14), therefore it can provide helpful data for the directed therapy against the gastric tumor.
Recently some reports showed HOXC13 is up-regulated in lung adenocarcinoma (15), prostate cancer (16), skin tumor (17), and squamous carcinoma (18). In agreement with our findings, Enteghami et al. (12) observed that the HOXC13 expression was significantly higher in colorectal tumor tissues compared to the normal adjacent tissues. HOXC13 exhibited a significant correlation with both distant metastasis and perineural invasion in our study. Similarly, Yao et al (15) stated that the expression of this gene was increased significantly in lung adenocarcinoma, and related to poorer prognosis and worse clinical features. It appeared that HOXC13 enhances progression and cell proliferation through up-regulation of CCNE1 and CCND1 (19). Besides, miR-141 was known to be able to impede the cell proliferation of lung adenocarcinoma via repressing the CCNE1, CCND1, and HOXC13 expression (20).
We also evaluated the HOTAIR expression in gastric tumors and explored its correlation with the clinicopathological properties. Our findings obviously displayed the increased HOTAIR expression in tumor tissue relative to non-tumor tissue. This finding in line with Endo et al. (21) who demonstrated up-regulation of the HOTAIR gene in gastric tumors in comparison with normal tissues. We did not find any correlation between HOTAIR expression and clinic-pathological properties. This is in line with observations of previous reports (22, 23, 24). Emadi-Andani et al. (11) also did not demonstrate a significant correlation between the clinic-pathological properties and the target gene expression. In contrast, Nie et al. (25) found that the HOTAIR expression is associated with lymph node metastasis and tumor stage. Moreover, according to our results the expression of HOXC13 and HOTAIR is moderately associated and therefore one of these genes can modulate the expressions of the other, and/or both genes can share regulatory mechanisms of expression. An association between HOXC13 and HOTAIR was also reported in breast and colorectal cancers (12 & 26). Of note, this gene can play a vital role in the progression of gastric tumors.
HOXC-AS3 can regulate a group of genes associated with gastric tumor migration and cell proliferation, such as HDAC5, WNT10B, and MMP7 by binding to YBX1 (4). Among these, HDAC5 is concerned as a vital gene belonging to the family histone deacetylase (4). Since the histone deacetylation/acetylation process is imperative for gene expression and chromatin remodeling, each imbalance in this process results in abnormal expression of tumor-associated genes (27). In addition to histone deacetylase 5, a couple of genes associated with tumorigenesis are modulated in a similar way by HOXC-AS3 lncRNA (28). Zhang et al (29) demonstrated that abnormal activity of HOXC-AS3 can induce cell migration and proliferation in gastric cancer through transcriptional activation of a large number of genes via interactions with YBX1. However, the HOXC-AS3 expression was insignificantly up-regulated in the tumor tissue in comparison to the marginal normal tissue in our study. Similarly, Enteghami et al. (12) showed the expression of HOXC-AS3 did not differ significantly in colorectal cancer compared to the normal adjacent tissues.
HOXC13-AS has been assumed to involve in the invasion and cell proliferation of nasopharyngeal carcinoma via miR-383-3p/ HMGA2 axis (30) and to denote a weak prognosis (31). This lncRNA accelerates the malignancy through the miR-378g/HOXC13 axis, presenting novel thought for facilitating the lncRNA-directed remedy of the cell carcinoma of oral squamous (32). However, the HOXC13-AS expression was insignificantly up-regulated in the tumor tissue compared to the marginal tissue in the present study. As a note, the HOXC13-AS gene showed a significant relationship with the sex factor, so that in females the expression of this gene was higher than in men.