Near-Infrared Luminescent Materials Incorporating Rare Earth/Transition Metal Ions: From Materials to Applications.

The spotlight has shifted to near-infrared (NIR) luminescent materials emitting beyond 1000 nm, with growing interest due to their unique characteristics. The ability of NIR-II emission (1000-1700 nm) to penetrate deeply and transmit independently positions these NIR luminescent materials for applications in optical-communication devices, bioimaging, and photodetectors. The combination of rare earth metals/transition metals with a variety of matrix materials provides a new platform for creating new chemical and physical properties for materials science and device applications. In this review, the recent advancements in NIR emission activated by rare earth and transition metal ions are summarized and their role in applications spanning bioimaging, sensing, and optoelectronics is illustrated. It started with various synthesis techniques and explored how rare earths/transition metals can be skillfully incorporated into various matrixes, thereby endowing them with unique characteristics. The discussion to strategies of enhancing excitation absorption and emission efficiency, spotlighting innovations like dye sensitization and surface plasmon resonance effects is then extended. Subsequently, a significant focus is placed on functionalization strategies and their applications. Finally, a comprehensive analysis of the challenges and proposed strategies for rare earth/transition metal ion-doped near-infrared luminescent materials, summarizing the insights of each section is provided.

WNT2-SOX4 positive feedback loop promotes chemoresistance and tumorigenesis by inducing stem-cell like properties in gastric cancer.

Gastric cancer (GC) is characterized by its vigorous chemoresistance to current therapies, which is attributed to the highly heterogeneous and immature phenotype of cancer stem cells (CSCs) during tumor initiation and progression. The secretory WNT2 ligand regulates multiple cancer pathways and has been demonstrated to be a potential therapeutic target for gastrointestinal tumors; however, its role involved in gastric CSCs (GCSCs) remains unclear. Here, we found that overexpression of WNT2 enhanced stemness properties to promote chemoresistance and tumorigenicity in GCSCs. Mechanistically, WNT2 was positively regulated by its transcription factor SOX4, and in turn, SOX4 was upregulated by the canonical WNT2/FZD8/ß-catenin signaling pathway to form an auto-regulatory positive feedback loop, resulting in the maintenance of GCSCs self-renewal and tumorigenicity. Furthermore, simultaneous overexpression of both WNT2 and SOX4 was correlated with poor survival and reduced responsiveness to chemotherapy in clinical GC specimens. Blocking WNT2 using a specific monoclonal antibody significantly disrupted the WNT2-SOX4 positive feedback loop in GCSCs and enhanced the chemotherapeutic efficacy when synergized with the chemo-drugs 5-fluorouracil and oxaliplatin in a GCSC-derived mouse xenograft model. Overall, this study identified a novel WNT2-SOX4 positive feedback loop as a mechanism for GCSCs-induced chemo-drugs resistance and suggested that the WNT2-SOX4 axis may be a potential therapeutic target for gastric cancer treatment.

Targeting LGSN restores sensitivity to chemotherapy in gastric cancer stem cells by triggering pyroptosis.

Gastric cancer (GC) is notoriously resistant to current therapies due to tumor heterogeneity. Cancer stem cells (CSCs) possess infinite self-renewal potential and contribute to the inherent heterogeneity of GC. Despite its crucial role in chemoresistance, the mechanism of stemness maintenance of gastric cancer stem cells (GCSCs) remains largely unknown. Here, we present evidence that lengsin, lens protein with glutamine synthetase domain (LGSN), a vital cell fate determinant, is overexpressed in GCSCs and is highly correlated with malignant progression and poor survival in GC patients. Ectopic overexpression of LGSN in GCSC-derived differentiated cells facilitated their dedifferentiation and treatment resistance by interacting with vimentin and inducing an epithelial-to-mesenchymal transition. Notably, genetic interference of LGSN effectively suppressed tumor formation by inhibiting GCSC stemness maintenance and provoking gasdermin-D-mediated pyroptosis through vimentin degradation/NLRP3 signaling. Depletion of LGSN combined with the chemo-drugs 5-fluorouracil and oxaliplatin could offer a unique and promising approach to synergistically rendering this deadly cancer eradicable in vivo. Our data place focus on the role of LGSN in GCSC regeneration and emphasize the critical importance of pyroptosis in battling GCSC.

Downregulation of MTAP promotes Tumor Growth and Metastasis by regulating ODC Activity in Breast Cancer.

5'-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway and has been reported to suppress tumorigenesis. The MTAP gene is located at 9p21, a chromosome region often deleted in breast cancer (BC). However, the clinical and biological significance of MTAP in BC is still unclear. Here, we reported that MTAP was frequently downregulated in 41% (35/85) of primary BCs and 89% (8/9) of BC cell lines. Low expression of MTAP was significantly correlated with a poor survival of BC patients (P=0.0334). Functional studies showed that MTAP was able to suppress both in vitro and in vivo tumorigenic ability of BC cells, including migration, invasion, angiogenesis, tumor growth and metastasis in nude mice with orthotopic xenograft tumor of BC. Mechanistically, we found that downregulation of MTAP could increase the polyamine levels by activating ornithine decarboxylase (ODC). By treating the MTAP-repressing BC cells with specific ODC inhibitor Difluoromethylornithine (DFMO) or treating the MTAP-overexpressing BC cells with additional putrescine, metastasis-promoting or -suppressing phenotype of these MTAP-manipulated cells was significantly reversed, respectively. Taken together, our data suggested that MTAP has a critical metastasis-suppressive role by tightly regulating ODC activity in BC cells, which may serve as a prominent novel therapeutic target for advanced breast cancer treatment.

miR-421 promotes the viability of A549 lung cancer cells by targeting forkhead box O1.

MicroRNA (miR)-421 has been reported to serve various important roles in numerous types of cancer, including neuroblastoma and gastric cancer. However, to the best of our knowledge, few reports have determined the role of miR-421 in lung cancer. The aim of the current study was to analyze the expression levels of miR-421 in A549 lung cancer cells, to determine the target gene of miR-421, and to investigate the function and mechanism of miR-421 in cellular cytotoxicity. miR-421 expression levels were analyzed in A549 lung cancer cells using reverse transcription-quantitative PCR, a MTT assay was performed to determine the effect of miR-421 on A549 cell cytotoxicity and the protein expression levels of forkhead box O1 (FOXO1) were determined via western blotting. The target gene of miR-421 was predicted and verified using TargetScan and a dual-luciferase reporter assay, respectively. The results revealed that miR-421 expression levels were significantly upregulated in A549 lung cancer cell lines compared with the normal cells (P<0.01). Additionally, it was discovered that miR-421 promoted A549 cell viability (P<0.01) compared with A549 transfected with negative control. miR-421 was also identified to bind to the 3'-untranslated region of FOXO1. In A549 cells transfected with miR-421-mimics, the expression levels of phosphorylated (p)-AKT, p-glycogen synthase kinase-3ß, p-retinoblastoma and cyclin D1 were significantly upregulated (P<0.01), whereas the expression levels of FOXO1 and p21 were significantly downregulated (P<0.01) compared with the control group. In conclusion, the results of the present study suggested that miR-421 may promote the viability of A549 lung cancer cells by targeting FOXO1 and modulating cell cycle, indicating that targeting miR-421 and FOXO1 may represent future therapeutic strategies for the treatment of patients with lung cancer.

Epigenetic alterations of a novel antioxidant gene SLC22A3 predispose susceptible individuals to increased risk of esophageal cancer.

Esophageal squamous cell carcinoma (ESCC) occurs with the highest frequency in China, especially in the high-risk Northern Chinese. Recent studies have reported that SLC22A3 is significantly downregulated in non-tumor (NT) esophageal tissues from familial ESCC patients compared with those from sporadic ESCC. However, the mechanism of how SLC22A3 regulates familial ESCC remains unknown. In this study, post hoc genome-wide association studies (GWAS) in 496 cases with a family history of upper gastrointestinal tract cancers and 1056 controls were performed and the results revealed that SLC22A3 is a novel susceptibility gene for familial ESCC. Reduced expression of SLC22A3 in NT esophageal tissues from familial ESCC patients significantly correlates with its promoter hypermethylation. Moreover, case-control study of Chinese descendants from different risk areas of China revealed that the methylation of the SLC22A3 gene in peripheral blood leukocyte (PBL) DNA samples could be a risk factor for developing ESCC in this high-risk population. Functional studies showed that SLC22A3 is a novel antioxidant gene, and deregulation of SLC22A3 facilitates heat stress-induced oxidative DNA damage and formation of γ-H2AX foci in normal esophageal epithelial cells. Collectively, we show that epigenetic alterations of SLC22A3 predispose susceptible individuals to increased risk of esophageal cancer.

Epigallocatechin-3-gallate Modulates MicroRNA Expression Profiles in Human Nasopharyngeal Carcinoma CNE2 Cells.

BACKGROUND: Epigallocatechin-3-gallate (EGCG) has exhibited antitumor properties in several types of cancers, including nasopharyngeal carcinoma (NPC), but the molecular mechanisms underlying this function remain incompletely understood. The aim of the present study was to characterize the global impact of EGCG on the expression of microRNAs (miRNAs) in NPC cells. METHODS: Using microarray analysis, the alterations of miRNA expression profiles were investigated in EGCG-treated CNE2 cells. Furthermore, the target genes and signaling pathways regulated by EGCG-specific miRNAs were identified using target prediction program and gene ontology analysis. RESULTS: A total of 14 miRNAs exhibited >2-fold expression changes in a dose-dependent manner after treatment with 20 µmol/L and 40 µmol/L EGCG. Totally 43, 49, and 52 target genes from these differentially expressed miRNAs were associated with the apoptosis, cell cycle regulation, and cell proliferation, respectively. A total of 66 signaling pathways, primarily involved in cancer development and lipid and glucose metabolism, were shown to be regulated by EGCG-specific miRNAs. CONCLUSION: EGCG induces considerable alterations of miRNA expression profiles in CNE2 cells, which provides mechanistic insights into cellular responses and antitumor activity mediated by EGCG.

Nemo-like kinase as a negative regulator of nuclear receptor Nurr1 gene transcription in prostate cancer.

BACKGROUND: Nurr1, a member of the orphan receptor family, plays an important role in several types of cancer. Our previous work demonstrated that increased expression of Nurr1 plays a significant role in the initiation and progression of prostate cancer (PCa), though the mechanisms for regulation of Nurr1 expression remain unknown. In this study, we investigated the hypothesis that Nemo-like kinase (NLK) is a key regulator of Nurr1 expression in PCa. METHODS: Immunohistochemistry and Western blot analysis were used to evaluate levels of NLK and Nurr1 in prostatic tissues and cell lines. The effects of overexpression or knockdown of Nurr1 were evaluated in PCa cells through use of PCR, Western blots and promoter reporter assays. The role of Nurr1 promoter cis element was studied by creation of two mutant Nurr1 promoter luciferase constructs, one with a mutated NF-κB binding site and one with a mutated CREB binding site. In addition, three specific inhibitors were used to investigate the roles of these proteins in transcriptional activation of Nurr1, including BAY 11-7082 (NF-κB inhibitor), KG-501 (CREB inhibitor) and ICG-001 (CREB binding protein, CBP, inhibitor). The function of CBP in NLK-mediated regulation of Nurr1 expression was investigated using immunofluorescence, co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation assays (ChIPs). RESULTS: NLK expression was inversely correlated with Nurr1 expression in prostate cancer tissues and cell lines. Overexpression of NLK suppressed Nurr1 promoter activity, leading to downregulation of Nurr1 expression. In contrast, knockdown of NLK demonstrated opposite results, leading to upregulation of Nurr1. When compared with the wild-type Nurr1 promoter, mutation of NF-κB- and CREB-binding sites of the Nurr1 promoter region significantly reduced the upregulation of Nurr1 induced by knockdown of NLK in LNCaP cells; treatment with inhibitors of CREB, CBP and NF-κB led to similar results. We also found that NLK directly interacts with CBP, that knockdown of NLK significantly increases the recruitment of CBP to both NF-κB- and CREB-binding sites, and that regulation of NLK on Nurr1 expression is abrogated by knockdown of CBP. CONCLUSIONS: Our results suggest that NLK inhibits transcriptional activation of Nurr1 gene by impeding CBP's role as a co-activator of NF-κB and CREB in prostate cancer.

Downregulation of GSK3ß by miR-544a to maintain self-renewal ability of lung caner stem cells.

In order to study the influence and mechanism of miR-544a on the self-renewal ability of lung cancer stem cells, TargetScan was used to predict the target gene of miR-544a. A luciferase reporter system and western blotting were used to validate the target genes identified by TargetScan. 95C and 95D low and high metastatic human lung cancer cells were transfected with miR-544a, and quantitative polymerase chain reaction (qPCR) was used to verify the miR-544a expression in these two cell lines. Tumor ball (spheroid) suspension culture was use to study the effects of miR-544a on lung cancer stem cells. TargetScan predicted that miR-544a interacted with GSK3ß. A luciferase reporter system (F=201.37, P<0.01) and western blot analysis was used to validate that miR-544a could inhibit the expression of GSK3ß, while ß-catenin and CD133 were significantly increased in miR-544a-overexpressing 95C and 95D cells (F=9.43, 7.73 and 3.37, respectively; P<0.01). qPCR revealed that miR-544a was overexpressed in transfected 95C and 95D cells (20.51±0.97 and 15.16±1.38, respectively; F=418.05; P<0.01). miR-544a-overexpressing cells formed spheroids in suspension cultures of spheroid single cells. miR-544a was shown to reduce the expression of GSK3ß and activate the Wnt signaling pathway to maintain the self-renewal ability of lung caner stem cells.

[Relationship between polymorphism sites of IRF5, TLR-9 and SLE patients in Shandong Han population].

OBJECTIVE: To investigate two single nucleotide polymorphism sites of IRF5 and TLR-9 and to detect their relationship with SLE (systemic lupus erythematosus) in a Han population from Shandong province. METHODS: The polymorphisms of rs2004640 G/T, rs10954213 G/A in IRF-5 and rs187084C/T, rs352139A/G in TLR-9 were detected with PCR-RFLP in 92 cases of SLE and 88 healthy controls. The genotype and allele frequencies were calculated and analyzed. RESULTS: (1) The genotype frequencies of GG, GT and TT in rs2004640 site in SLE were 0.198, 0.521 and 0.281 respectively. The difference was significant between SLE and controls (chi(2) = 8.73, P < 0.05); the genotype frequencies of GG, GA and AA at rs109542130 site in SLE were 0.318, 0.409 and 0.273 respectively. The difference was significant between SLE and controls (chi(2) = 6.36, P < 0.05). (2) The genotype frequencies of CC, CT and TT at rs187084 site in SLE were 0.185, 0.413 and 0.402 respectively. There was no difference between SLE and controls (chi(2) = 2.99, P > 0.05); the genotype frequencies of AA, AG and GG at rs352139 site in SLE were 0.228, 0.533 and 0.239 respectively. There was no difference between SLE and controls (chi(2) = 4.54, P > 0.05). CONCLUSION: The polymorphism of rs2004640 and rs10954213 in IRF5 may be associated with SLE in the population of Han nationality from Shandong province. However, the polymorphism of rs187084 and rs352139 in TLR-9 is not associated with SLE.