Expression and unique functions of four nuclear factor of activated T cells isoforms in non-small cell lung cancer

Abstract

Nuclear factor of activated T cells (NFAT) is an important family of transcription factors that can be activated by calmodulin and calcineurin in human cells. To investigate the expression and clinical significance of NFAT isoforms and calcineurin in non-small cell lung cancer (NSCLC), we collected tumor and adjacent normal tissues from 159 NSCLC patients and assembled them in a tissue microarray. Protein levels of NFAT1, NFAT2, NFAT3, NFAT4, and calcineurin were determined using immunohistochemistry. Correlations between NFAT and calcineurin expression and clinicopathologic characteristics were analyzed. We found that the positive rates of NFAT1 (52.8%, 84/159), NFAT2 (11.3%, 18/159), NFAT3 (28.3%, 45/ 159), NFAT4 (47.2%, 75/159), and calcineurin (47.8%, 76/159) expression were significantly higher in tumor tissues than in adjacent normal lung tissues (P < 0.001), respectively. The positive rate of NFAT1 expression was significantly higher in patients with adenocarcinoma (63.5%, 47/74) than in those with squamous cell carcinoma (43.5%, 37/85) (χ2 = 6.340, P = 0.012); with lymph node metastasis (61.6%, 53/ 86) than without lymph node metastasis (42.5%, 31/73) (χ2 = 5.818, P = 0.016); and with stage-ll and -III diseases (61.8%, 55/89) than with stage-I disease (41.4%, 29/70) (χ2 = 6.524, P = 0.011). Moreover, the overexpression of NFAT1 was associated with poor survival of NSCLC patients (χ2 = 5.006, P = 0.025). The positive rate of NFAT4 was significantly higher in patients with squamous carcinoma (57.6%, 49/85) than in those with adenocarcinoma (35.1%, 26/74) (χ2 = 8.045, P = 0.005) and with high and moderate differentiation (54.9%, 61/111) than with low differentiation (29.2%, 14/48) (χ2 = 8.943, P = 0.003). Calcineurin overexpression was significantly associated with histologic type (higher in squamous carcinoma than in adenocarcinoma, χ2 = 8.897, P = 0.003), differentiation grade (higher in high-moderation grade than in low grade, χ2 = 9.566, P = 0.002) and gender (higher in male than in female, χ2 = 5.766, P = 0.016). Furthermore, calcineurin expression was significantly correlated with NFAT4 level (r = 0.429, P < 0.001). These results suggest that NFAT1 expression is associated with lung adenocarcinoma progression, and NFAT4 expression, which was higher in squamous lung cancer, is associated with calcineurin expression and differentiation grade.

NFATc1 is a tumor suppressor in hepatocellular carcinoma and induces tumor cell apoptosis by activating the FasL‐mediated extrinsic signaling pathway

“…Over the past 20 years, the NFAT family has been shown to possess important functions, not only in immune cells but also in solid tissues and cells . Mounting evidence suggests the NFAT family plays a key role in many types of tumorigenesis . In this study, we first determined expression of NFAT family members in HCC and found that NFATc1 mRNA exhibited the biggest difference in expression levels between HCC and corresponding adjacent nontumor tissues.…”

“…Many studies suggest that NFAT not only regulates many kinds of immune cells but also functions in nonimmune cells, including the bone, heart, pancreas, and skin . Moreover, recent research found that NFAT regulated cell proliferation, invasion, differentiation, and angiogenesis in many types of cancer cells, including colon cancer, breast cancer, pancreatic cancer, lung cancer, ovarian cancer, and melanoma . However, little information is available regarding NFAT expression and function in HCC.…”

Transcription Factor NFAT1 Activates the mdm2 Oncogene Independent of p53

“…Baumgart et al (35) report that the NFAT1 protein levels are up-regulated in human advanced pancreatic cancer and positively related to disease progression. Chen et al (39) report that the positive rate of NFAT1 is significantly higher in non-small cell lung cancer tissues than adjacent normal lung tissues and also linked to disease progression and patient survival. However, Maxeiner et al (40) report that NFAT1 mRNA level is decreased in bronchial adenocarcinoma issues compared with control tissues and pneumonia tissues.…”

Nuclear factor of activated T cells in cancer development and treatment

“…Moreover, NFAT1 expression was significantly higher in patients with lymph node metastasis than without lymph node metastasis. Therefore, positive NFAT1 expression indicates a poor prognosis in lung cancer [73]. VEGFC and platelet-derived growth factor BB (PDGF-BB) have been extensively studied in lymphangiogenesis [94,95].…”

“…There are also several endogenous calcineurin inhibitors, including Down syndrome candidate region 1 (DSCR1), calcineurin-binding protein 1 (CABIN1), and A-kinase anchor protein 79 (AKAP79), as well as pharmacological calcineurin inhibitors: cyclosporine A (CsA) and tacrolimus (FK506), which bind to cyclophilin and FK506 binding protein (FKPB) respectively. [72,73]. Mechanistically, NFATs are transcription factors for invasion and migration-associated genes, such as cyclooxygenase-2 (COX-2) and autotaxin.…”