A Increased MRE11 mRNA expression in oral cancer tissues, in comparison to normal tissues, from our database. B Increased MRE11 mRNA expression in oral cancer tissues, in comparison to normal tissues, reported in online databases. C A negative correlation between MRE11A mRNA level and DNA methylation level in the putative promoter region of MRE11, reported in an online database. D Immunohistochemical staining for MRE11 protein expression in oral noncancerous and cancer tissues. E Quantitative result for MRE11 expression in oral noncancerous and cancer tissues. F Overall survival and progression-free survival for high and low MRE11 protein expression groups from our dataset. G Overall survival and progression-free survival for high and low MRE11 mRNA expression groups reported in an online database.

A Increased MRE11 mRNA expression in oral cancer tissues, in comparison to normal tissues, from our database. B Increased MRE11 mRNA expression in oral cancer tissues, in comparison to normal tissues, reported in online databases. C A negative correlation between MRE11A mRNA level and DNA methylation level in the putative promoter region of MRE11, reported in an online database. D Immunohistochemical staining for MRE11 protein expression in oral noncancerous and cancer tissues. E Quantitative result for MRE11 expression in oral noncancerous and cancer tissues. F Overall survival and progression-free survival for high and low MRE11 protein expression groups from our dataset. G Overall survival and progression-free survival for high and low MRE11 mRNA expression groups reported in an online database.

A Increased MRE11 mRNA expression in oral cancer tissues, in comparison to normal tissues, from our database. B Increased MRE11 mRNA expression in oral cancer tissues, in comparison to normal tissues, reported in online databases. C A negative correlation between MRE11A mRNA level and DNA methylation level in the putative promoter region of MRE11, reported in an online database. D Immunohistochemical staining for MRE11 protein expression in oral noncancerous and cancer tissues. E Quantitative result for MRE11 expression in oral noncancerous and cancer tissues. F Overall survival and progression-free survival for high and low MRE11 protein expression groups from our dataset. G Overall survival and progression-free survival for high and low MRE11 mRNA expression groups reported in an online database.

A MRE11 knockdown decreased, while its overexpression increased, wound closure in oral cancer cells. B MRE11 knockdown decreased, while its overexpression increased, transwell migration in oral cancer cells. C MRE11 knockdown decreased, while its overexpression increased, transwell invasion in oral cancer cells. D MRE11 knockdown decreased, while its overexpression increased, epithelial-to-mesenchymal transition in oral cancer cells. E Mirin, a MRE11 nuclease inhibitor, increased the expression of γH2AX, an indicator of DSB, in oral cancer cells upon ionizing radiation exposure. F Mirin treatment did not inhibit the proliferation-promoting activity of MRE11 in oral cancer cells. G Mirin treatment did not inhibit the migration-promoting activity of MRE11 in oral cancer cells. H Nuclease-deficient MRE11 with H129N mutation showed proliferation-promoting activity. I Nuclease-deficient MRE11 with H129N mutation showed migration-promoting activity.

A MRE11 knockdown decreased, while its overexpression increased, wound closure in oral cancer cells. B MRE11 knockdown decreased, while its overexpression increased, transwell migration in oral cancer cells. C MRE11 knockdown decreased, while its overexpression increased, transwell invasion in oral cancer cells. D MRE11 knockdown decreased, while its overexpression increased, epithelial-to-mesenchymal transition in oral cancer cells. E Mirin, a MRE11 nuclease inhibitor, increased the expression of γH2AX, an indicator of DSB, in oral cancer cells upon ionizing radiation exposure. F Mirin treatment did not inhibit the proliferation-promoting activity of MRE11 in oral cancer cells. G Mirin treatment did not inhibit the migration-promoting activity of MRE11 in oral cancer cells. H Nuclease-deficient MRE11 with H129N mutation showed proliferation-promoting activity. I Nuclease-deficient MRE11 with H129N mutation showed migration-promoting activity.

A MRE11 knockdown decreased, while its overexpression increased, wound closure in oral cancer cells. B MRE11 knockdown decreased, while its overexpression increased, transwell migration in oral cancer cells. C MRE11 knockdown decreased, while its overexpression increased, transwell invasion in oral cancer cells. D MRE11 knockdown decreased, while its overexpression increased, epithelial-to-mesenchymal transition in oral cancer cells. E Mirin, a MRE11 nuclease inhibitor, increased the expression of γH2AX, an indicator of DSB, in oral cancer cells upon ionizing radiation exposure. F Mirin treatment did not inhibit the proliferation-promoting activity of MRE11 in oral cancer cells. G Mirin treatment did not inhibit the migration-promoting activity of MRE11 in oral cancer cells. H Nuclease-deficient MRE11 with H129N mutation showed proliferation-promoting activity. I Nuclease-deficient MRE11 with H129N mutation showed migration-promoting activity.

A MRE11 knockdown decreased, while its overexpression increased, wound closure in oral cancer cells. B MRE11 knockdown decreased, while its overexpression increased, transwell migration in oral cancer cells. C MRE11 knockdown decreased, while its overexpression increased, transwell invasion in oral cancer cells. D MRE11 knockdown decreased, while its overexpression increased, epithelial-to-mesenchymal transition in oral cancer cells. E Mirin, a MRE11 nuclease inhibitor, increased the expression of γH2AX, an indicator of DSB, in oral cancer cells upon ionizing radiation exposure. F Mirin treatment did not inhibit the proliferation-promoting activity of MRE11 in oral cancer cells. G Mirin treatment did not inhibit the migration-promoting activity of MRE11 in oral cancer cells. H Nuclease-deficient MRE11 with H129N mutation showed proliferation-promoting activity. I Nuclease-deficient MRE11 with H129N mutation showed migration-promoting activity.

A The effect of MRE11 knockdown and overexpression on colony formation in oral cancer cells after ionizing radiation exposure. B The effect of MRE11 knockdown and overexpression on comet tail formation, an indicator for DSBs, in oral cancer cells after ionizing radiation treatment. C The effect of MRE11 knockdown and overexpression on γH2AX expression, an indicator for DSBs, in oral cancer cells after ionizing radiation exposure. D The effect of MRE11 knockdown and overexpression on oral cancer cell apoptosis, determined by TUNEL positivity, after ionizing radiation treatment. E The effect of MRE11 knockdown and overexpression on oral cancer cell apoptosis, determined by Annexin V positivity, after ionizing radiation treatment. F The effect of MRE11 expression, determined by IHC, on overall survival of oral cancer patients after radiotherapy.

A The effect of MRE11 knockdown and overexpression on colony formation in oral cancer cells after ionizing radiation exposure. B The effect of MRE11 knockdown and overexpression on comet tail formation, an indicator for DSBs, in oral cancer cells after ionizing radiation treatment. C The effect of MRE11 knockdown and overexpression on γH2AX expression, an indicator for DSBs, in oral cancer cells after ionizing radiation exposure. D The effect of MRE11 knockdown and overexpression on oral cancer cell apoptosis, determined by TUNEL positivity, after ionizing radiation treatment. E The effect of MRE11 knockdown and overexpression on oral cancer cell apoptosis, determined by Annexin V positivity, after ionizing radiation treatment. F The effect of MRE11 expression, determined by IHC, on overall survival of oral cancer patients after radiotherapy.

A MRE11 knockdown led to decreased RUNX2 expression, while MRE11 overexpression led to increased RUNX2 expression, in oral cancer cells. B The correlation of RUNX2 expression in oral cancer tissues with MRE11 expression and lymph node metastasis in oral cancer patients. C A positive correlation between RUNX2 and CXCR4 expression in oral cancer tissues. D CXCR4 expression in oral cancer cells was decreased when MRE11 was knockdowned. E MRE11 and CXCR4 were positively correlated in primary oral cancer tissues and CXCR4 was more highly expressed in oral cancer tissues with lymph node metastasis. F MRE11 knockdown led to decreased pAKT expression, while MRE11 overexpression led to increased pAKT expression, in oral cancer cells. G The correlation between MRE11 and pAKT expression in oral cancer tissues. H Wortmannin, a PI3K/AKT inhibitor, reversed the increased oral cancer migration induced by MRE11 overexpression. I CXCR4 silencing reversed the increased pAKT expression caused by MRE11 overexpression. J CXCR4 blocking mAb reversed the increased pAKT expression caused by SDF-1, a CXCR4 activator, in MRE11-overexpressing oral cancer cells. K MRE11 knockdown in oral cancer cells led to increased expression of nuclear FOXA2, which was partially reversed by cotreatment with AKT activator SC79. L MRE11 overexpression in oral cancer cells decreased the nuclear expression of FOXA2 while treatment with wortmannin reversed the increased nuclear expression of FOXA2 induced by MRE11 overexpression. M Correlation of MRE11 and FOXA2 expression in oral cancer tissues and metastatic lymph nodes. N Correlation of phospho-AKT and FOXA2 expression in oral cancer tissues and metastatic lymph nodes.

A MRE11 knockdown led to decreased RUNX2 expression, while MRE11 overexpression led to increased RUNX2 expression, in oral cancer cells. B The correlation of RUNX2 expression in oral cancer tissues with MRE11 expression and lymph node metastasis in oral cancer patients. C A positive correlation between RUNX2 and CXCR4 expression in oral cancer tissues. D CXCR4 expression in oral cancer cells was decreased when MRE11 was knockdowned. E MRE11 and CXCR4 were positively correlated in primary oral cancer tissues and CXCR4 was more highly expressed in oral cancer tissues with lymph node metastasis. F MRE11 knockdown led to decreased pAKT expression, while MRE11 overexpression led to increased pAKT expression, in oral cancer cells. G The correlation between MRE11 and pAKT expression in oral cancer tissues. H Wortmannin, a PI3K/AKT inhibitor, reversed the increased oral cancer migration induced by MRE11 overexpression. I CXCR4 silencing reversed the increased pAKT expression caused by MRE11 overexpression. J CXCR4 blocking mAb reversed the increased pAKT expression caused by SDF-1, a CXCR4 activator, in MRE11-overexpressing oral cancer cells. K MRE11 knockdown in oral cancer cells led to increased expression of nuclear FOXA2, which was partially reversed by cotreatment with AKT activator SC79. L MRE11 overexpression in oral cancer cells decreased the nuclear expression of FOXA2 while treatment with wortmannin reversed the increased nuclear expression of FOXA2 induced by MRE11 overexpression. M Correlation of MRE11 and FOXA2 expression in oral cancer tissues and metastatic lymph nodes. N Correlation of phospho-AKT and FOXA2 expression in oral cancer tissues and metastatic lymph nodes.

A MRE11 knockdown led to decreased RUNX2 expression, while MRE11 overexpression led to increased RUNX2 expression, in oral cancer cells. B The correlation of RUNX2 expression in oral cancer tissues with MRE11 expression and lymph node metastasis in oral cancer patients. C A positive correlation between RUNX2 and CXCR4 expression in oral cancer tissues. D CXCR4 expression in oral cancer cells was decreased when MRE11 was knockdowned. E MRE11 and CXCR4 were positively correlated in primary oral cancer tissues and CXCR4 was more highly expressed in oral cancer tissues with lymph node metastasis. F MRE11 knockdown led to decreased pAKT expression, while MRE11 overexpression led to increased pAKT expression, in oral cancer cells. G The correlation between MRE11 and pAKT expression in oral cancer tissues. H Wortmannin, a PI3K/AKT inhibitor, reversed the increased oral cancer migration induced by MRE11 overexpression. I CXCR4 silencing reversed the increased pAKT expression caused by MRE11 overexpression. J CXCR4 blocking mAb reversed the increased pAKT expression caused by SDF-1, a CXCR4 activator, in MRE11-overexpressing oral cancer cells. K MRE11 knockdown in oral cancer cells led to increased expression of nuclear FOXA2, which was partially reversed by cotreatment with AKT activator SC79. L MRE11 overexpression in oral cancer cells decreased the nuclear expression of FOXA2 while treatment with wortmannin reversed the increased nuclear expression of FOXA2 induced by MRE11 overexpression. M Correlation of MRE11 and FOXA2 expression in oral cancer tissues and metastatic lymph nodes. N Correlation of phospho-AKT and FOXA2 expression in oral cancer tissues and metastatic lymph nodes.

A MRE11 knockdown led to decreased RUNX2 expression, while MRE11 overexpression led to increased RUNX2 expression, in oral cancer cells. B The correlation of RUNX2 expression in oral cancer tissues with MRE11 expression and lymph node metastasis in oral cancer patients. C A positive correlation between RUNX2 and CXCR4 expression in oral cancer tissues. D CXCR4 expression in oral cancer cells was decreased when MRE11 was knockdowned. E MRE11 and CXCR4 were positively correlated in primary oral cancer tissues and CXCR4 was more highly expressed in oral cancer tissues with lymph node metastasis. F MRE11 knockdown led to decreased pAKT expression, while MRE11 overexpression led to increased pAKT expression, in oral cancer cells. G The correlation between MRE11 and pAKT expression in oral cancer tissues. H Wortmannin, a PI3K/AKT inhibitor, reversed the increased oral cancer migration induced by MRE11 overexpression. I CXCR4 silencing reversed the increased pAKT expression caused by MRE11 overexpression. J CXCR4 blocking mAb reversed the increased pAKT expression caused by SDF-1, a CXCR4 activator, in MRE11-overexpressing oral cancer cells. K MRE11 knockdown in oral cancer cells led to increased expression of nuclear FOXA2, which was partially reversed by cotreatment with AKT activator SC79. L MRE11 overexpression in oral cancer cells decreased the nuclear expression of FOXA2 while treatment with wortmannin reversed the increased nuclear expression of FOXA2 induced by MRE11 overexpression. M Correlation of MRE11 and FOXA2 expression in oral cancer tissues and metastatic lymph nodes. N Correlation of phospho-AKT and FOXA2 expression in oral cancer tissues and metastatic lymph nodes.

A The effect of MRE11 knockdown in oral cancer cells on orthotopic oral tumor volume. B The effect of MRE11 knockdown in oral cancer cells on weekly total flux of orthotopic oral tumors. C The effect of MRE11 knockdown in oral cancer cells on total flux of orthotopic oral tumors at sacrifice. D–I The effect of MRE11 knockdown in oral cancer cells on the expression of MRE11, Ki67, RUNX2, CXCR4, pAKT, and FOXA2 in oral tumor tissues. J An example of CLN metastasis shown by IVIS imaging and H&E stain. K Quantitative data of CLN metastasis in mice when MRE11 expression in oral cancer cells was knockdowned.

A The effect of MRE11 knockdown in oral cancer cells on orthotopic oral tumor volume. B The effect of MRE11 knockdown in oral cancer cells on weekly total flux of orthotopic oral tumors. C The effect of MRE11 knockdown in oral cancer cells on total flux of orthotopic oral tumors at sacrifice. D–I The effect of MRE11 knockdown in oral cancer cells on the expression of MRE11, Ki67, RUNX2, CXCR4, pAKT, and FOXA2 in oral tumor tissues. J An example of CLN metastasis shown by IVIS imaging and H&E stain. K Quantitative data of CLN metastasis in mice when MRE11 expression in oral cancer cells was knockdowned.

A An example of oral cancer cell migration in zebrafish. B Quantitation of the effects of MRE11 knockdown and overexpression in oral cancer cells on migration in zebrafish model. C The effect of MRE11 overexpression in oral cancer cells on total flux of lung metastasis. D The effect of MRE11 overexpression in oral cancer cells on metastatic lung tumor area. E–H The effect of MRE11 overexpression in oral cancer cells on the expression of MRE11, RUNX2, CXCR4, and pAKT in metastatic lung tumor tissues. I CXCR4 neutralizing antibody reverse the cancer metastasis promoted by MRE11 overexpression in mouse model. Representative microscopic views of the lung sections. Hematoxylin-positive blue-colored nodules indicate metastatic colony number (Student’s t test) and tumor area (%) (Mann–Whitney U test). J Schematic diagram for MRE11 signaling pathway and activity.

A An example of oral cancer cell migration in zebrafish. B Quantitation of the effects of MRE11 knockdown and overexpression in oral cancer cells on migration in zebrafish model. C The effect of MRE11 overexpression in oral cancer cells on total flux of lung metastasis. D The effect of MRE11 overexpression in oral cancer cells on metastatic lung tumor area. E–H The effect of MRE11 overexpression in oral cancer cells on the expression of MRE11, RUNX2, CXCR4, and pAKT in metastatic lung tumor tissues. I CXCR4 neutralizing antibody reverse the cancer metastasis promoted by MRE11 overexpression in mouse model. Representative microscopic views of the lung sections. Hematoxylin-positive blue-colored nodules indicate metastatic colony number (Student’s t test) and tumor area (%) (Mann–Whitney U test). J Schematic diagram for MRE11 signaling pathway and activity.