Nuclear factor of activated T-cells, cytoplasmic 4 (NFATc4), a transcription factor of NFAT family, which is activated by Ca²⁺/calcineurin signaling. Recently, it is reported that aberrantly activated NFATc4 participated and modulated in the initiation, proliferation, invasion, and metastasis of various cancers (including cancers of the lung, breast, ovary, cervix, skin, liver, pancreas, as well as glioma, primary myelofibrosis and acute myelocytic leukemia). In this review, we cover the latest knowledge on NFATc4 expression pattern, post-translational modification, epigenetic regulation, transcriptional activity regulation and its downstream targets. Furthermore, we perform database analysis to reveal the prognostic value of NFATc4 in various cancers and discuss the current unexplored areas of NFATc4 research. All in all, the result from these studies strongly suggest that NFATc4 has the potential as a molecular therapeutic target in multiple human cancer types.

The synergistic anticancer effect of gemcitabine (GEM) and resveratrol (RSVL) has been noted in certain cancer types. However, whether the same phenomenon would occur in lung cancer is unclear. Here, we uncovered the molecular mechanism by which RSVL enhances the anticancer effect of GEM against lung cancer cells both in vitro and in vivo. We established human lung adenocarcinoma HCC827 xenografts in nude mice and treated them with GEM and RSVL to detect their synergistic effect in vivo. Tumor tissue sections from nude mice were subjected to hematoxylin and eosin staining for blood vessel morphological observation, and immunohistochemistry was conducted to detect CD31-positive staining blood vessels. We also established the HCC827-human umbilical vein endothelial cell (HUVEC) co-culture model to observe the tubule network formation. Human angiogenesis antibody array was used to screen the angiogenesis-related proteins in RSVL-treated HCC827. RSVL suppressed the expression of endoglin (ENG) and increased tumor microvessel growth and blood perfusion into tumor. Co-treatment of RSVL and GEM led to more tumor growth suppression than treatment of GEM alone. Mechanistically, using the HCC827-HUVEC co-culture model, we showed that RSVL-suppressed ENG expression was accompanied with augmented levels of phosphorylated extracellular signal-regulated kinase (ERK) 1/2 and increased tubule network formation, which may explain why RSVL promoted tumor microvessel growth in vivo. RSVL promoted tumor microvessel growth via ENG and ERK and enhanced the anticancer efficacy of GEM. Our results suggest that intake of RSVL may be beneficial during lung cancer chemotherapy.

Quantum dots (QDs) are luminescent nanoparticles with superior versatility. In this regard, cadmium telluride (CdTe) QDs have been widely used for various bioimaging applications. Although these nano-Cd containing particles can be capped with shells to reduce their cytotoxicity, these shells would be gradually disintegrated after a certain period of time, thereby inevitably exerting nanotoxicity. Previously, we showed that treatment of human bronchial epithelial BEAS-2B cells with uncapped CdTe QDs (520Q, 580Q and 730Q with emission maximum at 520, 580 and 730 nm, respectively) elicited dose-dependent cytotoxicity for 520Q and 580Q (5 nm) elicited negligible cytotoxicity. In order to gain a more global perspective on the action mechanism of these nano-Cd particles, here, we further characterized the proteome response of BEAS-2B when challenged with the above QDs. Interestingly, among the three nano-Cd particles, we observed that 520Q and 580Q treatment altered the BEAS-2B proteome significantly in a very similar magnitude while 730Q has no obvious impact at all, as compared with the untreated control. Notably, the treatment of BEAS-2B with glutathione before nano-Cd particles abrogated the induction/repression of differentially expressed proteins and prevented cell death. Taken together, our findings show that uncapped CdTe nanoparticles (520Q and 580Q) induce oxidative stress in human bronchial epithelial cells, and the similarly altered protein signatures also suggest potential mitotoxicity and common cellular and detoxification responses upon exposure of lung cells to these two QDs. On the other hand, 730Q may exert a more noticeable effect after long-term exposure, but not upon transient exposure.

The cytochrome P450s (CYP450s) include key oxidative enzymes involved in the metabolism of various carcinogens and anticancer drugs. Bioinformatic studies have demonstrated the association of CYP3A43 with liver cancer and ovarian cancer. However, the biological function of CYP3A43 in tumor progression remains unclear. To further reveal the role of CYP3A43 in tumor progression, we first analyzed the data from the UALCAN database and found that CYP3A43 was negatively correlated to the cancer staging and lymph node metastasis of lung adenocarcinoma (LUAD). We established stable CYP3A43-knockdown LUAD H1299 cell line and found that its knockdown enhanced cell proliferation, colony formation, and migration in vitro, and promoted the growth of tumor xenograft in vivo. Interestingly, when CYP3A43 was ectopically-expressed in the LUAD cell lines, decreased cell proliferation and ERK1/2 phosphorylation level were observed. Lastly, we also identified CYP3A43 co-expressed genes in LUAD from LinkedOmics database followed by GO and KEGG analyses. In conclusion, our results indicate the unprecedented role of CYP3A43 in the suppression of LUAD and provide new possibilities for targeted therapy of this life-threatening disease.

Cytochrome P450 enzymes (CYP450s) exert mighty catalytic actions in cellular metabolism and detoxication, which play pivotal roles in cell fate determination. Preliminary data shows differential expression levels of CYP27C1, one of the “orphan P450s” in human lung cancer cell lines. Here, we study the functions of CYP27C1 in lung cancer progression and drug endurance, and explore its potential to be a diagnostic and therapeutic target for lung cancer management. Quantitative real-time PCR and immunoblot assays were conducted to estimate the transcription and protein expression level of CYP27C1 in human lung cancer cell lines, which was relatively higher in A549 and H1975 cells, but was lower in H460 cells. Stable CYP27C1-knockdown A549 and H1975 cell lines were established, in which these cells showed enhancement in cell proliferation, colony formation, and migration. In addition, aberrant IGF-1R/Akt/p53 signal transduction was also detected in stable CYP27C1-knockdown human lung cancer cells, which exhibited greater tolerance towards the treatments of anticancer agents (including vinorelbine, picropodophyllin, pacritinib, and SKLB610). This work, for the first time, reveals that CYP27C1 impacts lung cancer cell development by participating in the regulation of the IGF-1R/Akt/p53 signaling pathway, and the level of CYP27C1 plays indispensable roles in dictating the cellular sensitivity towards multiple anticancer agents.

Studying the relatively underexplored atypical MAP Kinase MAPK15 on cancer progression/patient outcomes and its potential transcriptional regulation of downstream genes would be highly valuable for the diagnosis, prognosis, and potential oncotherapy of malignant tumors such as lung adenocarcinoma (LUAD). Here, the expression of MAPK15 in LUAD was detected by immunohistochemistry and its correlation with clinical parameters such as lymph node metastasis and clinical stage was analyzed. The correlation between the prostaglandin E2 receptor EP3 subtype (EP3) and MAPK15 expression in LUAD tissues was examined, and the transcriptional regulation of EP3 and cell migration by MAPK15 in LUAD cell lines were studied using the luciferase reporter assay, immunoblot analysis, qRT-PCR, and transwell assay. We found that MAPK15 is highly expressed in LUAD with lymph node metastasis. In addition, EP3 is positively correlated with the expression of MAPK15 in LUAD tissues, and we confirmed that MAPK15 transcriptionally regulates the expression of EP3. Upon the knockdown of MAPK15, the expression of EP3 was down-regulated and the cell migration ability was decreased in vitro; similarly, the mesenteric metastasis ability of the MAPK15 knockdown cells was inhibited in in vivo animal experiments. Mechanistically, we demonstrate for the first time that MAPK15 interacts with NF-κB p50 and enters the nucleus, and NF-κB p50 binds to the EP3 promoter and transcriptionally regulates the expression of EP3. Taken together, we show that a novel atypical MAPK and NF-κB subunit interaction promotes LUAD cell migration through transcriptional regulation of EP3, and higher MAPK15 level is associated with lymph node metastasis in patients with LUAD.