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PAK1-mediated MORC2 phosphorylation promotes gastric tumorigenesis.

Wang G, Song Y, Liu T, Wang C, Zhang Q, Liu F, Cai X, Miao Z, Xu H, Xu H, Cao L, Li F - Oncotarget (2015)

Bottom Line: To date, microrchidia (MORC) family CW-type zinc-finger 2 (MORC2), has been found to be involved in p21-activated kinase1 (PAK1) pathway to maintain genomic integrity.We demonstrate that PAK1-mediated MORC2 phosphorylation promotes cell cycle progression, defective phosphorylation of MORC2-S677A results in attenuated cell proliferation and tumorigenicity of gastric cancer cells, which is significantly enhanced in overexpression of phospho-mimic MORC2-S677E form, suggesting the importance of MORC2 phosphorylation in tumorigenesis.Collectively, these findings revealed a novel function of MORC2 phosphorylation in promoting gastric cell proliferation in vitro and tumorigenesis in vivo, suggesting that blocking PAK1-mediated MORC2 phosphorylation might be a potential therapeutic strategy for gastric tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China.

ABSTRACT
To date, microrchidia (MORC) family CW-type zinc-finger 2 (MORC2), has been found to be involved in p21-activated kinase1 (PAK1) pathway to maintain genomic integrity. Here, we explore its novel role in cancer. We demonstrate that PAK1-mediated MORC2 phosphorylation promotes cell cycle progression, defective phosphorylation of MORC2-S677A results in attenuated cell proliferation and tumorigenicity of gastric cancer cells, which is significantly enhanced in overexpression of phospho-mimic MORC2-S677E form, suggesting the importance of MORC2 phosphorylation in tumorigenesis. More importantly, phosphorylation of MORC2 correlates positively with PAK1 expression in clinical gastric cancer. Furthermore, high expression of PAK1 and phosphorylation of MORC2 appear to be associated with poor prognosis of clinical gastric cancer. Collectively, these findings revealed a novel function of MORC2 phosphorylation in promoting gastric cell proliferation in vitro and tumorigenesis in vivo, suggesting that blocking PAK1-mediated MORC2 phosphorylation might be a potential therapeutic strategy for gastric tumorigenesis.

No MeSH data available.


Related in: MedlinePlus

Phosphorylation of MORC2 and PAK1 expression positively correlates with clinical gastric cancer outcome(A) Evaluate the expression of the PAK1 and p-MORC2 in clinical tissues by western Blot. Lysates of 68 cancer tissues (C) and matched adjacent normal tissues (N) pairs were analyzed by Western Blot. Number of cancers with reduced or increased levels of indicated protein relative to normal adjacent tissues and analyze with GAPDH as the reference. The representative 10 pairs were shown. (B) Summary of the expression in tissues in (a) is shown, with tissues categorized by lower and higher expression. The expression of PAK1 and p-MORC2 Ser677 was analyzed with GAPDH as the reference. In each N and C pair, the lower/higher expression in C, compared with N, is categorized as lower/higher expression. The P value was generated using the chi-square test. (C) Representative images of immunohistochemical staining of PAK1 and p-MORC2 expression from one case were shown. The boxed areas in the left images are magnified in the right images. N, adjacent normal tissue (shown in the left column); C, cancer tissue (shown in the right column). Original magnification, ×200. (D) Box plot of PAK1 and p-MORC2 1 expressions were shown. The subjects were divided into two groups based on PAK1 expression scores in the 210 gastric tumors, representing low and high expression. The PAK1 and p-MORC2 expression scores were shown as box plots, with the horizontal lines representing the median; the bottom and top of the boxes representing the 25th and 75th percentiles, respectively; and the vertical bars representing the range of data. And extreme cases were marked with a dot. Data was analyzed by one-way analysis of variance (ANOVA) test with Games–Howell's correction. (E) Kaplan–Meier's analyses illustrated that the 5-year survival rate according to PAK1 and p-MORC2 expression scores, representing low and high expression of them. These 210 gastric cancer patients were divided into four groups based on PAK1 and p-MORC2 expression scores, the higher and lower of expression of PAK1 and p-MORC2 were analyzed by Kaplan–Meier analysis.
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Figure 5: Phosphorylation of MORC2 and PAK1 expression positively correlates with clinical gastric cancer outcome(A) Evaluate the expression of the PAK1 and p-MORC2 in clinical tissues by western Blot. Lysates of 68 cancer tissues (C) and matched adjacent normal tissues (N) pairs were analyzed by Western Blot. Number of cancers with reduced or increased levels of indicated protein relative to normal adjacent tissues and analyze with GAPDH as the reference. The representative 10 pairs were shown. (B) Summary of the expression in tissues in (a) is shown, with tissues categorized by lower and higher expression. The expression of PAK1 and p-MORC2 Ser677 was analyzed with GAPDH as the reference. In each N and C pair, the lower/higher expression in C, compared with N, is categorized as lower/higher expression. The P value was generated using the chi-square test. (C) Representative images of immunohistochemical staining of PAK1 and p-MORC2 expression from one case were shown. The boxed areas in the left images are magnified in the right images. N, adjacent normal tissue (shown in the left column); C, cancer tissue (shown in the right column). Original magnification, ×200. (D) Box plot of PAK1 and p-MORC2 1 expressions were shown. The subjects were divided into two groups based on PAK1 expression scores in the 210 gastric tumors, representing low and high expression. The PAK1 and p-MORC2 expression scores were shown as box plots, with the horizontal lines representing the median; the bottom and top of the boxes representing the 25th and 75th percentiles, respectively; and the vertical bars representing the range of data. And extreme cases were marked with a dot. Data was analyzed by one-way analysis of variance (ANOVA) test with Games–Howell's correction. (E) Kaplan–Meier's analyses illustrated that the 5-year survival rate according to PAK1 and p-MORC2 expression scores, representing low and high expression of them. These 210 gastric cancer patients were divided into four groups based on PAK1 and p-MORC2 expression scores, the higher and lower of expression of PAK1 and p-MORC2 were analyzed by Kaplan–Meier analysis.

Mentions: To further study the role of MORC2 phosphorylation in gastric cancer, we analyzed levels of PAK1and phosphorylated MORC2, by western blotting, in 68 pairs of gastric cancers and matched adjacent normal gastric tissue samples. The results incidated that overexpression of both p-MORC2 and PAK1 was observed in 44% (30 of 68) of gastric cancer, and neither of these two proteins presented higher expression in 23.5% (16 of 68) of tumors. MORC2 was phosphorylated in 71% (30 of 42) of gastric cancer with overexpressed PAK1 patients (Figure 5A). Statistical analysis revealed p-MORC2 expression positively correlated with PAK1 expression (p = 0.007; Figure 5B) in gastric cancer tissues, which are consistent with our findings that overexpression of PAK1 upregulated p-MORC2 in gastric cell lines (Figure 2).


PAK1-mediated MORC2 phosphorylation promotes gastric tumorigenesis.

Wang G, Song Y, Liu T, Wang C, Zhang Q, Liu F, Cai X, Miao Z, Xu H, Xu H, Cao L, Li F - Oncotarget (2015)

Phosphorylation of MORC2 and PAK1 expression positively correlates with clinical gastric cancer outcome(A) Evaluate the expression of the PAK1 and p-MORC2 in clinical tissues by western Blot. Lysates of 68 cancer tissues (C) and matched adjacent normal tissues (N) pairs were analyzed by Western Blot. Number of cancers with reduced or increased levels of indicated protein relative to normal adjacent tissues and analyze with GAPDH as the reference. The representative 10 pairs were shown. (B) Summary of the expression in tissues in (a) is shown, with tissues categorized by lower and higher expression. The expression of PAK1 and p-MORC2 Ser677 was analyzed with GAPDH as the reference. In each N and C pair, the lower/higher expression in C, compared with N, is categorized as lower/higher expression. The P value was generated using the chi-square test. (C) Representative images of immunohistochemical staining of PAK1 and p-MORC2 expression from one case were shown. The boxed areas in the left images are magnified in the right images. N, adjacent normal tissue (shown in the left column); C, cancer tissue (shown in the right column). Original magnification, ×200. (D) Box plot of PAK1 and p-MORC2 1 expressions were shown. The subjects were divided into two groups based on PAK1 expression scores in the 210 gastric tumors, representing low and high expression. The PAK1 and p-MORC2 expression scores were shown as box plots, with the horizontal lines representing the median; the bottom and top of the boxes representing the 25th and 75th percentiles, respectively; and the vertical bars representing the range of data. And extreme cases were marked with a dot. Data was analyzed by one-way analysis of variance (ANOVA) test with Games–Howell's correction. (E) Kaplan–Meier's analyses illustrated that the 5-year survival rate according to PAK1 and p-MORC2 expression scores, representing low and high expression of them. These 210 gastric cancer patients were divided into four groups based on PAK1 and p-MORC2 expression scores, the higher and lower of expression of PAK1 and p-MORC2 were analyzed by Kaplan–Meier analysis.
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Related In: Results  -  Collection

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Figure 5: Phosphorylation of MORC2 and PAK1 expression positively correlates with clinical gastric cancer outcome(A) Evaluate the expression of the PAK1 and p-MORC2 in clinical tissues by western Blot. Lysates of 68 cancer tissues (C) and matched adjacent normal tissues (N) pairs were analyzed by Western Blot. Number of cancers with reduced or increased levels of indicated protein relative to normal adjacent tissues and analyze with GAPDH as the reference. The representative 10 pairs were shown. (B) Summary of the expression in tissues in (a) is shown, with tissues categorized by lower and higher expression. The expression of PAK1 and p-MORC2 Ser677 was analyzed with GAPDH as the reference. In each N and C pair, the lower/higher expression in C, compared with N, is categorized as lower/higher expression. The P value was generated using the chi-square test. (C) Representative images of immunohistochemical staining of PAK1 and p-MORC2 expression from one case were shown. The boxed areas in the left images are magnified in the right images. N, adjacent normal tissue (shown in the left column); C, cancer tissue (shown in the right column). Original magnification, ×200. (D) Box plot of PAK1 and p-MORC2 1 expressions were shown. The subjects were divided into two groups based on PAK1 expression scores in the 210 gastric tumors, representing low and high expression. The PAK1 and p-MORC2 expression scores were shown as box plots, with the horizontal lines representing the median; the bottom and top of the boxes representing the 25th and 75th percentiles, respectively; and the vertical bars representing the range of data. And extreme cases were marked with a dot. Data was analyzed by one-way analysis of variance (ANOVA) test with Games–Howell's correction. (E) Kaplan–Meier's analyses illustrated that the 5-year survival rate according to PAK1 and p-MORC2 expression scores, representing low and high expression of them. These 210 gastric cancer patients were divided into four groups based on PAK1 and p-MORC2 expression scores, the higher and lower of expression of PAK1 and p-MORC2 were analyzed by Kaplan–Meier analysis.
Mentions: To further study the role of MORC2 phosphorylation in gastric cancer, we analyzed levels of PAK1and phosphorylated MORC2, by western blotting, in 68 pairs of gastric cancers and matched adjacent normal gastric tissue samples. The results incidated that overexpression of both p-MORC2 and PAK1 was observed in 44% (30 of 68) of gastric cancer, and neither of these two proteins presented higher expression in 23.5% (16 of 68) of tumors. MORC2 was phosphorylated in 71% (30 of 42) of gastric cancer with overexpressed PAK1 patients (Figure 5A). Statistical analysis revealed p-MORC2 expression positively correlated with PAK1 expression (p = 0.007; Figure 5B) in gastric cancer tissues, which are consistent with our findings that overexpression of PAK1 upregulated p-MORC2 in gastric cell lines (Figure 2).

Bottom Line: To date, microrchidia (MORC) family CW-type zinc-finger 2 (MORC2), has been found to be involved in p21-activated kinase1 (PAK1) pathway to maintain genomic integrity.We demonstrate that PAK1-mediated MORC2 phosphorylation promotes cell cycle progression, defective phosphorylation of MORC2-S677A results in attenuated cell proliferation and tumorigenicity of gastric cancer cells, which is significantly enhanced in overexpression of phospho-mimic MORC2-S677E form, suggesting the importance of MORC2 phosphorylation in tumorigenesis.Collectively, these findings revealed a novel function of MORC2 phosphorylation in promoting gastric cell proliferation in vitro and tumorigenesis in vivo, suggesting that blocking PAK1-mediated MORC2 phosphorylation might be a potential therapeutic strategy for gastric tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China.

ABSTRACT
To date, microrchidia (MORC) family CW-type zinc-finger 2 (MORC2), has been found to be involved in p21-activated kinase1 (PAK1) pathway to maintain genomic integrity. Here, we explore its novel role in cancer. We demonstrate that PAK1-mediated MORC2 phosphorylation promotes cell cycle progression, defective phosphorylation of MORC2-S677A results in attenuated cell proliferation and tumorigenicity of gastric cancer cells, which is significantly enhanced in overexpression of phospho-mimic MORC2-S677E form, suggesting the importance of MORC2 phosphorylation in tumorigenesis. More importantly, phosphorylation of MORC2 correlates positively with PAK1 expression in clinical gastric cancer. Furthermore, high expression of PAK1 and phosphorylation of MORC2 appear to be associated with poor prognosis of clinical gastric cancer. Collectively, these findings revealed a novel function of MORC2 phosphorylation in promoting gastric cell proliferation in vitro and tumorigenesis in vivo, suggesting that blocking PAK1-mediated MORC2 phosphorylation might be a potential therapeutic strategy for gastric tumorigenesis.

No MeSH data available.


Related in: MedlinePlus