Combined overexpression of cadherin 6, cadherin 11 and cluster of differentiation 44 is associated with lymph node metastasis and poor prognosis in oral squamous cell carcinoma
Abstract:Oral squamous cell carcinoma (OSCC) is a highly invasive lesion that frequently metastasizes to the cervical lymph nodes and is associated with a poor prognosis. Several adhesion factors, including cadherin 6 (CDH6), cadherin 11 (CDH11) and cluster of differentiation 44 (CD44), have been reported to be involved in the invasion and metastasis of multiple types of cancer. Therefore, the aim of the present study was to determine the expression of CDH6, CDH11 and CD44 in tumor tissues from patients with OSCC, and … Show more
“…CXCL12 derived from tumor fibroblasts is known to promote tumor-cell invasion in breast cancer 55,56. CDH11, an adhesion molecule, is involved in pancreatic cell migration,57 and its overexpression, combined with Cdh6 and CD44, is associated with lymph-node metastases and poor prognosis in oral carcinoma 58. Finally, MYCL1 has not been reported to play a role in metastasis, but is recurrently amplified in Merkel-cell carcinoma59 and its genetic deletion in lung cancer models leads to strong tumor suppression 60…”
IntroductionMetastasis involves the accumulation of genetic and epigenetic alterations leading to activation of prometastatic genes and inactivation of antimetastatic genes. Among epigenetic alterations, DNA hypermethylation and histone hypoacetylation are the focus of intense translational research because their pharmacological inhibition has been shown to produce antineoplastic activity in a variety of experimental models.AimsThis study aimed to evaluate the antimetastatic effect of the DNA-methylation inhibitor, hydralazine, and the histone deacetylase inhibitor, valproic acid.MethodsNIH 3T3-Ras murine cells were treated with hydralazine and valproic acid to evaluate their effects upon cell proliferation, cell motility, chemotaxis, gelatinase activity, and gene expression. Lung metastases were developed by intravenous injection of NIH 3T3-Ras cells in BALB/c nu/nu mice and then treated with the drug combination.ResultsTreatment induced a growth-inhibitory effect on NIH 3T3-Ras cells, showed a trend toward increased gelatinase activity of MMP2 and MMP9, and inhibited chemotaxis and cell motility. The combination led to a strong antimetastatic effect in lungs of nude mice.ConclusionHydralazine and valproic acid, two repositioned drugs as epigenetic agents, exhibit antimetastatic effects in vitro and in vivo and hold potential for cancer treatment.
“…CXCL12 derived from tumor fibroblasts is known to promote tumor-cell invasion in breast cancer 55,56. CDH11, an adhesion molecule, is involved in pancreatic cell migration,57 and its overexpression, combined with Cdh6 and CD44, is associated with lymph-node metastases and poor prognosis in oral carcinoma 58. Finally, MYCL1 has not been reported to play a role in metastasis, but is recurrently amplified in Merkel-cell carcinoma59 and its genetic deletion in lung cancer models leads to strong tumor suppression 60…”
IntroductionMetastasis involves the accumulation of genetic and epigenetic alterations leading to activation of prometastatic genes and inactivation of antimetastatic genes. Among epigenetic alterations, DNA hypermethylation and histone hypoacetylation are the focus of intense translational research because their pharmacological inhibition has been shown to produce antineoplastic activity in a variety of experimental models.AimsThis study aimed to evaluate the antimetastatic effect of the DNA-methylation inhibitor, hydralazine, and the histone deacetylase inhibitor, valproic acid.MethodsNIH 3T3-Ras murine cells were treated with hydralazine and valproic acid to evaluate their effects upon cell proliferation, cell motility, chemotaxis, gelatinase activity, and gene expression. Lung metastases were developed by intravenous injection of NIH 3T3-Ras cells in BALB/c nu/nu mice and then treated with the drug combination.ResultsTreatment induced a growth-inhibitory effect on NIH 3T3-Ras cells, showed a trend toward increased gelatinase activity of MMP2 and MMP9, and inhibited chemotaxis and cell motility. The combination led to a strong antimetastatic effect in lungs of nude mice.ConclusionHydralazine and valproic acid, two repositioned drugs as epigenetic agents, exhibit antimetastatic effects in vitro and in vivo and hold potential for cancer treatment.
“…However, those genes were not detected at 8 weeks after PHMG exposure. Meanwhile, at 8 weeks after PHMG exposure, lung cancer-related genes such as TOP2A and MKI67 and tumor metastasis-related genes such as CDH11 and CD44 were significantly upregulated 12 – 15 . Figure 4 Analysis of PHMG-regulated gene expression in rat lung tissue.…”
Our aim was to correlate chest CT and pathologic findings of polyhexamethylene guanidine phosphate (PHMG)-induced lung injuries in a rat model, to determine whether PHMG exposure causes lung tumors, and to explore genetic alterations according to PHMG exposure under the guidance of CT. A PHMG solution was intratracheally administrated to 40 male rats. Chest CT was carried out in all rats and both lungs were collected for histopathologic evaluation. At 4- and 8-weeks post-instillation, one lobe of the right lung from 3 rats was subjected to RNA sequencing. At least one abnormal CT finding was found in all rats at all weeks. The major CT findings were inflammation, fibrosis, and tumors in the pathologic analysis, where significant changes were observed over time. The lung lesions remained persistent after 8 weeks of PHMG exposure. In the pathologic analysis, the extent/severity of inflammation did not show statistically significant changes over time, whereas the extent/severity of fibrosis increased continuously up to 6 weeks after PHMG exposure and then decreased significantly at 8 weeks. Bronchiolar-alveolar adenomas which have malignant potential were found in 50% of rats at 6 and 8 weeks after PHMG exposure. Also, several genes associated with lung cancer, acute lung injury, and pulmonary fibrosis were detected. Our study revealed that PHMG-induced lung injury and its changes according to the number of weeks after exposure were demonstrated using chest CT and pathologic evaluation. In addition, we showed that PHMG exposure caused lung tumors and genetic alterations according to PHMG exposure under the guidance of CT.
“…There are additional studies suggesting that CDH6 is an important EMT marker in PTC as it can promote PTC metastasis by participating in the regulation of autophagy, thus leading to a poor prognosis [39]. Ma et al suggest that CDH6 is signi cantly up-regulated in patients with lymph node metastasis in oral squamous cell carcinoma (OSCC) and that patients have a poor prognosis [40]. It was further suggested that, when combined with other adhesion factor-related genes, CDH6 can be used as an important biomarker for OSCC lymph node metastasis and prognosis [40].…”
Section: Discussionmentioning
confidence: 99%
“…Ma et al suggest that CDH6 is signi cantly up-regulated in patients with lymph node metastasis in oral squamous cell carcinoma (OSCC) and that patients have a poor prognosis [40]. It was further suggested that, when combined with other adhesion factor-related genes, CDH6 can be used as an important biomarker for OSCC lymph node metastasis and prognosis [40]. An in vivo study by Karthikeyan et al con rmed that CDH6 was inhibited by mutant p53 in high-grade serous ovarian cancer, which suggests that CDH6 may be a biomarker for this condition [41].…”
Background: While cadherin (CDH) genes are aberrantly expressed in cancers, the functions of CDH genes in gastric cancer (GC) remain poorly understood. The clinical significance and molecular mechanisms of CDH genes in GC were assessed in this study.Methods: Data from a total of 1226 GC patients included in The Cancer Genome Atlas (TCGA) and Kaplan-Meier plotter database were used to independently explore the value of CDH genes in clinical application. The TCGA RNA sequencing dataset was used to explore the molecular mechanisms of CDH genes in GC.Results: Using enrichment analysis tools, CDH genes were found to be related to cell adhesion and calcium ion binding in function. In TCGA cohort, 12 genes were found to be differentially expressed between GC para-carcinoma and tumor tissue. By analyzing GC patients in two independent cohorts, we identified and verified that CDH2, CDH6, CDH7 and CDH10 were significantly associated with a poor GC prognosis. In addition, CDH2 and CDH6 were used to construct a GC risk score signature that can significantly improve the accuracy of predicting the 5-year survival of GC patients. The GSEA approach was used to explore the functional mechanisms of the four prognostic CDH genes and their associated risk scores. It was found that these genes may be involved in multiple classic cancer-related signaling pathways, such as the Wnt and phosphoinositide 3-kinase signaling pathways in GC. In the subsequent CMap analysis, three small molecule compounds (anisomycin, nystatin and bumetanide) that may be the target molecules that determine the risk score in GC, were initially screened. Conclusions: Our current study suggests that four CDH genes can be used as potential biomarkers for GC prognosis. In addition, a prognostic signature based on the CDH2 and CDH6 genes was constructed, and their potential functional mechanisms and drug interactions explored.
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