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Cldn1

Official Full Name
claudin 1
Background
Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. These junctions are comprised of sets of continuous networking strands in the outwardly facing cytoplasmic leaflet, with complementary grooves in the inwardly facing extracytoplasmic leaflet. The protein encoded by this gene, a member of the claudin family, is an integral membrane protein and a component of tight junction strands. Loss of function mutations result in neonatal ichthyosis-sclerosing cholangitis syndrome.
Synonyms
CLDN1; claudin 1; claudin-1; ILVASC; SEMP1; senescence associated epithelial membrane protein 1; senescence-associated epithelial membrane protein 1; CLD1; CLD1, SEMP1, ILVASC; tight junction protein; cldn19; claudin 19

Recent Research Progress

Claudin 1 (CLDN1) is one of the intact membrane proteins that make up tight junctions. Tight junctions are critical for tight sealing of cell sheets and maintaining homeostasis. The lack of tight junctions or defective tight junctions is associated with the development of tumor phenotypes in epithelial cells. Therefore, it is acceptable that the destruction of tight junctions leads to loss of cohesion, invasiveness and lack of differentiation, thereby promoting tumorigenesis.

CLDN1 and HCC

Recent studies have found that miR-29a was down-regulation and CLDN-1 was up-regulation in hepatocellular carcinoma (HCC) tissues and cell lines. It was further found that the expression of miR-29a and CLDN1 was inversely related in HCC. The dual luciferase reporter assay indicated that miR-29a regulates the expression of CLDN1 by binding to its 3'-untranslated region (3'UTR). Knockdown of CLDN1 resulted in decreased ability of tumor cell growth and migration in vitro and in vivo . Although overexpression of miR-29a inhibited tumor growth and migration, these effects could be reversed by re-expressing CLDN1. Taken together, the data suggested that miR-29a can provide a promising therapeutic target for HCC by targeting tumor growth and migration by targeting CLDN1.

CLDN1 and GC

In gastric cancer (GC), it has been reported that the regulation of CLDN1 is associated with transformation in invasive front and metastatic lesion. Recently, studies have found that CLDN1 small interfering RNA (siRNA) transfection significantly inhibited cell migration and invasion in gastric cancer cells. Furthermore, microarray analysis revealed that down-regulation of CLDN1 altered the expression levels of many genes associated with cell motility and tumor necrosis factor alpha (TNF-alpha) signaling. In conclusion, CLDN1 plays an important role in TNF-α-induced gastric cancer cell gene expression and cell movement.

CLDN1 and lung adenocarcinoma

Adenocarcinoma is the most common histological subtype of lung cancer. The dysfunction of the airway epithelial barrier has been reported to be associated with the development and progression of cancer, including lung cancer. Multivariate analysis showed that the prognostic factors of lung adenocarcinoma were histological type, CLDN1, T stage and N stage. Patients with positive CLDN1 expression had a worse prognosis than patients with negative CLDN1 expression. CLDN1 expression was associated with Ras and epidermal growth factor receptor (EGFR) expression. Patients with positive expression of CLDN1 and Ras/EGFR were worse than patients with negative expression of CLDN1 (+) Ras/EGFR (-) or CLDN1 (-) Ras/EGFR (+) and CLDN1 and Ras/EGFR. Compared with the lung adenocarcinoma cell line (A549), the expression of CLDN1 mRNA was lower in formerly bronchioloalveolar carcinoma (H358). These data suggest that the combination of CLDN1 and Ras/EGFR is a valuable independent prognostic predictor of lung adenocarcinoma.

CLDN1 and NSCLC

Non-small cell lung cancer (NSCLC) remains the most common cause of cancer death worldwide. Approximately 85% of total lung malignancies are non-small cells, and approximately 40% of NSCLC patients show locally advanced or metastatic disease at the time of diagnosis. Recently, CLDN1 was identified as a novel target for miR-375 in NSCLC and it was found that high miR-375 expression leads to a shortened survival of NSCLC patients. Overexpression of miR-375 promotes cell migration, indicating high invasion and metastasis potential in NSCLC expressing high levels of miR-375. Further research is needed to elucidate the function of miR-375 and CLDN1 in NSCLC.

CLDN1 and cervical cancer

Although human papillomavirus (HPV) is very important, it is not the only cause of cervical cancer. Recently, Zhang et al. found that the copy number and protein expression of CLDN1 increased with the progression of cervical cancer. The strong positive staining of CLDN1 in the cervical lymph node metastasis group was significantly higher than that in the cervical lymph node metastasis group. Overexpression of CLDN1 in SiHa cells increases anti-apoptotic ability and promotes the invasive ability of these cells, while the expression of the epithelial marker E-cadherin is decreased and the expression of mesenchymal marker vimentin is increased. CLDN1 induces epithelial-mesenchymal transition (EMT) through its interaction with SNAI1. Furthermore, CLDN1 overexpression has a significant effect on the growth and metastasis of xenograft tumors in athymic mice. These data indicate that CLDN1 promotes invasion and metastasis of cervical cancer cells through the expression of EMT/invasion-related genes. Therefore, CLDN1 may be a potential therapeutic target for the treatment of cervical cancer.

CLDN1 and OS

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents, often accompanied by lung metastasis, indicating poor clinical outcomes. It was reported that CLDN1 is increased in metastatic OS cells (KRIB and KHOS) compared to normal osteoblasts (hFOB1 .19) or primary tumor cells (HOS and U2OS), whereas no significant difference was found in Occludin and ZO-1. Immunohistochemistry, immunofluorescence and Western blotting showed that CLDN1 was originally localized to the cell junction of normal osteoblasts, but substantially delocalized to the nucleus of metastatic OS cells. Phenotypically, inhibition of the nucleus CLDN1 expression compromised the metastatic potential of KRIB and KHOS cells. Moreover, protein kinase C (PKC) but not PKA phosphorylation affected CLDN1 expression and cellular function, as PKC inhibitor (Go 6983 and Staurosporine) or genetic silencing of PKC reduced CLDN1 expression and decreased the motility of KRIB and KHOS cells. In conclusion, the delocalization of CLDN1 induced by PKC phosphorylation contributes to the ability of OS cells to metastasize.

CLDN1 and breast cancer

Breast cancer has high morbidity and high mortality worldwide. Several viral vectors, including lentivirus, adenovirus and adeno-associated viral vectors, have been used for gene therapy of various forms of human cancer, and have shown promising effects in controlling tumor progression. Zhao et al. tested the therapeutic potential of silencing CLDN1 expression in two breast cancer (MDA-MB-231 and MCF7) cell lines using lentiviral vector-mediated RNA interference. The CLDN1 short hairpin (shRNA) construct was found to efficiently silence CLDN1 expression in both breast cancer cell lines, and CLDN1 knockdown resulted in decreased cell proliferation, survival, migration and invasion. In addition, by up-regulating the epithelial cell marker E-cadherin and down-regulating mesenchymal markers, smooth muscle cells α-actin (SMA) and Snai2, silencing CLDN1 inhibits epithelial to mesenchymal transition (EMT). The data suggest that lentiviral vector-mediated CLDN1 RNA interference has great potential in breast cancer gene therapy by inhibiting EMT and controlling tumor cell growth.

In summary, CLDN1 can positively and negatively regulate tumorigenesis in different human cancer types. Therefore, further research to understand the biological role of CLDN1 in tumor cell migration and invasion ability is of great significance for the prevention and treatment of cancer.

References:

  1. Huang jie, et al. The expression of Claudin 1 correlates with β-catenin and is a prognostic factor of poor outcome in gastric cancer. International Journal Of Oncology, 2014, 44:1293-1301
  2. Atsushi Shiozaki, et al. Claudin 1 mediates tumor necrosis factor alpha-induced cell migration in human gastric cancer cells. World J Gastroenterol, 2014, 20(47): 17863-17876
  3. Judit Moldvay, et al. Claudin-1 Protein Expression Is a Good Prognostic Factor in Non-Small Cell Lung Cancer, but only in Squamous Cell Carcinoma Cases. Pathoogy & Oncology Research, 2017, 23(1): 151-156
  4. Satoshi Yoda, et al. Claudin-1 is a novel target of miR-375 in non-small-cell lung cancer. Lung Cancer, 2014, 85:366–372
  5. Huang Jie, et al. Claudin-1 enhances tumor proliferation and metastasis by regulating cell anoikis in gastric cancer. Oncotarget, 2015, 6(3): 1652-1665
  6. Sun Bingsheng, et al. Claudin-1 correlates with poor prognosis in lung adenocarcinoma. Thoracic Cancer, 2016, 7:556–563
  7. Zhao Xianqi, et al. Lentiviral Vector Mediated Claudin1 Silencing Inhibits Epithelial to Mesenchymal Transition in Breast Cancer Cells. Viruses-Basel, 2015, 7(6): 2965-2979
  8. Fei Ma, et al. A CLDN1-Negative Phenotype Predicts Poor Prognosis in Triple-Negative Breast Cancer. PLoS ONE, 2014, 9(11): e112765.
  9. Jian Yuekui, et al. Delocalized Claudin-1 promotes metastasis of human osteosarcoma cells. Biochemical and Biophysical Research Communications, 2015, 466:356e361
  10. Zhang Weina, et al. CLDN1 expression in cervical cancer cells is related to tumor invasion and metastasis. Oncotarget, 2016, 7(52):87449-87461

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