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Chloride channel-3 promotes tumor metastasis by regulating membrane ruffling and is associated with poor survival.

Xu B, Jin X, Min L, Li Q, Deng L, Wu H, Lin G, Chen L, Zhang H, Li C, Wang L, Zhu J, Wang W, Chu F, Shen J, Li H, Mao J - Oncotarget (2015)

Bottom Line: High-grade expression of cytoplasmic ClC-3 predicted poor survival in cancer patients.We found that independent of its volume-activated Cl- channel properties, ClC-3 was able to promote cell membrane ruffling, required for tumor metastasis.ClC-3 mediated membrane ruffling by regulating keratin 18 phosphorylation to control β1 Integrin recycling.

View Article: PubMed Central - PubMed

Affiliation: Guangdong Key Laboratory for Bioactive Drugs Research, Guangdong Pharmaceutical University, Guangzhou, China.

ABSTRACT
The chloride channel-3 (ClC-3) protein is known to be a component of Cl- channels involved in cell volume regulation or acidification of intracellular vesicles. Here, we report that ClC-3 was highly expressed in the cytoplasm of metastatic carcinomatous cells and accelerated cell migration in vitro and tumor metastasis in vivo. High-grade expression of cytoplasmic ClC-3 predicted poor survival in cancer patients. We found that independent of its volume-activated Cl- channel properties, ClC-3 was able to promote cell membrane ruffling, required for tumor metastasis. ClC-3 mediated membrane ruffling by regulating keratin 18 phosphorylation to control β1 Integrin recycling. Therefore, cytoplasmic ClC-3 plays an active and key role in tumor metastasis and may be a valuable prognostic biomarker and a therapeutic target to prevent tumor spread.

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Association between ClC-3 Expression and Tumor Metastasis or Survival in Cancer Patients(A-C) Analyses of ClC-3 Expression Difference between Primary and Metastatic Tumors. Overview of immunohistochemical staining of ClC-3 in a tissue microarray section containing 30 pairs of primary pulmonary adenocarcinoma and their matched lymph node metastatic tumors (A) .1: primary tumor; 2: adjacent non-neoplastic tissue; 3: matched lymph node metastatic tumor. Representative immunohistochemical images for ClC-3 sampled from tissue microarray of rectal adenocarcinoma, breast ductal carcinoma and esophageal squamous cell carcinoma (B). Summary of higher expression percentage of cytoplasmic ClC-3 in metastatic tumors compared to the corresponding primary tumors (C). (D-I) Association between cytoplasmic or nuclear ClC-3 expression and survival in primary carcinomas. Kaplan–Meier survival estimates for high- and intermediate- or low-grade cases of lung (D), breast (F) and liver (H) cancer regarding cytoplasmic ClC-3 expression. Kaplan–Meier survival curves were generated to assess differences between high- and intermediate- or low-grade nuclear ClC-3 expression cases of lung (E), breast (G) and liver (I) cancer.
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Figure 1: Association between ClC-3 Expression and Tumor Metastasis or Survival in Cancer Patients(A-C) Analyses of ClC-3 Expression Difference between Primary and Metastatic Tumors. Overview of immunohistochemical staining of ClC-3 in a tissue microarray section containing 30 pairs of primary pulmonary adenocarcinoma and their matched lymph node metastatic tumors (A) .1: primary tumor; 2: adjacent non-neoplastic tissue; 3: matched lymph node metastatic tumor. Representative immunohistochemical images for ClC-3 sampled from tissue microarray of rectal adenocarcinoma, breast ductal carcinoma and esophageal squamous cell carcinoma (B). Summary of higher expression percentage of cytoplasmic ClC-3 in metastatic tumors compared to the corresponding primary tumors (C). (D-I) Association between cytoplasmic or nuclear ClC-3 expression and survival in primary carcinomas. Kaplan–Meier survival estimates for high- and intermediate- or low-grade cases of lung (D), breast (F) and liver (H) cancer regarding cytoplasmic ClC-3 expression. Kaplan–Meier survival curves were generated to assess differences between high- and intermediate- or low-grade nuclear ClC-3 expression cases of lung (E), breast (G) and liver (I) cancer.

Mentions: Our previous studies found that down-regulation of ClC-3 expression reduce cancer cell migration [26, 32]. These suggested that elevated expression of ClC-3 may be associated with an increased metastatic capacity of primary human cancer. To test this hypothesis, we evaluated ClC-3 expression in several types of cancers including lung, stomach, colon, rectum, esophagus, breast and cervix carcinoma by immunostaining. In 272 pairs of primary tumors and their matched metastatic tumors, ClC-3 expression could be detected mainly in the cytoplasm and some in both cytoplasm and nucleus (Figure 1A, B and S3A). Comparing the expression between primary tumors and their matched metastatic tumors, cytoplasm expression of ClC-3 in 181 of 272 (69.8%) pairs of tumors was clearly higher in metastatic tumors than in their corresponding primary tumors (Figure 1A-C).


Chloride channel-3 promotes tumor metastasis by regulating membrane ruffling and is associated with poor survival.

Xu B, Jin X, Min L, Li Q, Deng L, Wu H, Lin G, Chen L, Zhang H, Li C, Wang L, Zhu J, Wang W, Chu F, Shen J, Li H, Mao J - Oncotarget (2015)

Association between ClC-3 Expression and Tumor Metastasis or Survival in Cancer Patients(A-C) Analyses of ClC-3 Expression Difference between Primary and Metastatic Tumors. Overview of immunohistochemical staining of ClC-3 in a tissue microarray section containing 30 pairs of primary pulmonary adenocarcinoma and their matched lymph node metastatic tumors (A) .1: primary tumor; 2: adjacent non-neoplastic tissue; 3: matched lymph node metastatic tumor. Representative immunohistochemical images for ClC-3 sampled from tissue microarray of rectal adenocarcinoma, breast ductal carcinoma and esophageal squamous cell carcinoma (B). Summary of higher expression percentage of cytoplasmic ClC-3 in metastatic tumors compared to the corresponding primary tumors (C). (D-I) Association between cytoplasmic or nuclear ClC-3 expression and survival in primary carcinomas. Kaplan–Meier survival estimates for high- and intermediate- or low-grade cases of lung (D), breast (F) and liver (H) cancer regarding cytoplasmic ClC-3 expression. Kaplan–Meier survival curves were generated to assess differences between high- and intermediate- or low-grade nuclear ClC-3 expression cases of lung (E), breast (G) and liver (I) cancer.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385862&req=5

Figure 1: Association between ClC-3 Expression and Tumor Metastasis or Survival in Cancer Patients(A-C) Analyses of ClC-3 Expression Difference between Primary and Metastatic Tumors. Overview of immunohistochemical staining of ClC-3 in a tissue microarray section containing 30 pairs of primary pulmonary adenocarcinoma and their matched lymph node metastatic tumors (A) .1: primary tumor; 2: adjacent non-neoplastic tissue; 3: matched lymph node metastatic tumor. Representative immunohistochemical images for ClC-3 sampled from tissue microarray of rectal adenocarcinoma, breast ductal carcinoma and esophageal squamous cell carcinoma (B). Summary of higher expression percentage of cytoplasmic ClC-3 in metastatic tumors compared to the corresponding primary tumors (C). (D-I) Association between cytoplasmic or nuclear ClC-3 expression and survival in primary carcinomas. Kaplan–Meier survival estimates for high- and intermediate- or low-grade cases of lung (D), breast (F) and liver (H) cancer regarding cytoplasmic ClC-3 expression. Kaplan–Meier survival curves were generated to assess differences between high- and intermediate- or low-grade nuclear ClC-3 expression cases of lung (E), breast (G) and liver (I) cancer.
Mentions: Our previous studies found that down-regulation of ClC-3 expression reduce cancer cell migration [26, 32]. These suggested that elevated expression of ClC-3 may be associated with an increased metastatic capacity of primary human cancer. To test this hypothesis, we evaluated ClC-3 expression in several types of cancers including lung, stomach, colon, rectum, esophagus, breast and cervix carcinoma by immunostaining. In 272 pairs of primary tumors and their matched metastatic tumors, ClC-3 expression could be detected mainly in the cytoplasm and some in both cytoplasm and nucleus (Figure 1A, B and S3A). Comparing the expression between primary tumors and their matched metastatic tumors, cytoplasm expression of ClC-3 in 181 of 272 (69.8%) pairs of tumors was clearly higher in metastatic tumors than in their corresponding primary tumors (Figure 1A-C).

Bottom Line: High-grade expression of cytoplasmic ClC-3 predicted poor survival in cancer patients.We found that independent of its volume-activated Cl- channel properties, ClC-3 was able to promote cell membrane ruffling, required for tumor metastasis.ClC-3 mediated membrane ruffling by regulating keratin 18 phosphorylation to control β1 Integrin recycling.

View Article: PubMed Central - PubMed

Affiliation: Guangdong Key Laboratory for Bioactive Drugs Research, Guangdong Pharmaceutical University, Guangzhou, China.

ABSTRACT
The chloride channel-3 (ClC-3) protein is known to be a component of Cl- channels involved in cell volume regulation or acidification of intracellular vesicles. Here, we report that ClC-3 was highly expressed in the cytoplasm of metastatic carcinomatous cells and accelerated cell migration in vitro and tumor metastasis in vivo. High-grade expression of cytoplasmic ClC-3 predicted poor survival in cancer patients. We found that independent of its volume-activated Cl- channel properties, ClC-3 was able to promote cell membrane ruffling, required for tumor metastasis. ClC-3 mediated membrane ruffling by regulating keratin 18 phosphorylation to control β1 Integrin recycling. Therefore, cytoplasmic ClC-3 plays an active and key role in tumor metastasis and may be a valuable prognostic biomarker and a therapeutic target to prevent tumor spread.

Show MeSH
Related in: MedlinePlus