SPI1-Mediated Upregulation of the CST1 Gene as an Independent Poor Prognostic Factor Accelerates Metastasis in Esophageal Squamous Cell Carcinoma (ESCC) by Interacting with MMP2.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a highly lethal tumor type, but studies on the ESCC tumor microenvironment are limited. We found that cystatin SN (CST1) plays an important role in the ESCC tumor microenvironment. CST1 has been reported to act as an oncogene in multiple human cancers, but its clinical significance and underlying mechanism in ESCC remain elusive. METHODS: We performed ESCC gene expression profiling with data from RNA-sequencing and public databases and found CST1 upregulation in ESCC. Then, we assessed CST1 expression in ESCC by RT‒qPCR and Western blot analysis. In addition, immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA) were used to estimate the expression of CST1 in ESCC tissue and serum. Moreover, further functional experiments were conducted to verify that the gain and loss of CST1 in ESCC cell lines significantly influenced the proliferation and metastasis of ESCC. Mass spectrometry, coimmunoprecipitation, and gelatin zymography experiments were used to validate the interaction between CST1 and matrix metalloproteinase 2 (MMP2) and the mechanism of CST1 influence on metastasis in ESCC. RESULTS: Here, we found that CST1 expression was significantly elevated in ESCC tissues and serum. Moreover, compared with patients with low CST1 expression, patients with high CST1 expression had a worse prognosis. Overall survival (OS) and disease-free survival (DFS) were significantly unfavorable in the high CST1 expression subgroup. Likewise, the CST1 level was significantly increased in ESCC serum compared with healthy control serum, indicating that CST1 may be a potential serum biomarker for diagnosis, with an area under the curve (AUC) = 0.9702 and p < 0.0001 by receiver operating curve (ROC) analysis. Furthermore, upregulated CST1 can promote the motility and metastatic capacity of ESCC in vitro and in vivo by influencing epithelial mesenchymal transition (EMT) and interacting with MMP2 in the tumor microenvironment (TME). CONCLUSIONS: Collectively, the results of this study indicated that high CST1 expression mediated by SPI1 in ESCC may serve as a potentially prognostic and diagnostic predictor and as an oncogene to promote motility and metastatic capacity of ESCC by influencing EMT and interacting with MMP2 in the TME.

Novel long noncoding RNA LINC02820 augments TNF signaling pathway to remodel cytoskeleton and potentiate metastasis in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors in China. However, there are no targets to treat ESCC because the molecular mechanism behind the cancer is still unclear. Here, we found a novel long noncoding RNA LINC02820 was upregulated in ESCC and associated with the ESCC clinicopathological stage. Through a series of functional experiments, we observed that LINC02820 only promoted the migration and invasion capabilities of ESCC cell lines. Mechanically, we found that LINC02820 may affect the cytoskeletal remodeling, interact with splice factor 3B subunit 3 (SF3B3), and cooperate with TNFα to amplify the NF-κB signaling pathway, which can lead to ESCC metastasis. Overall, our findings revealed that LINC02820 is a potential biomarker and therapeutic target for the diagnosis and treatment of ESCC.

Terahertz non-label subwavelength imaging with composite photonics-plasmonics structured illumination.

Inspired by the capability of structured illumination microscopy (SIM) in subwavelength imaging, many researchers devoted themselves to investigating this methodology. However, due to the free-propagating feature of the traditional structured illumination fields, the resolution can be only improved up to two-fold of the diffraction-limited microscopy. Besides, most of the previous studies, relying on incoherent illumination sources, are restricted to fluorescent samples. In this work, a subwavelength non-fluorescent imaging method is proposed based on the illumination of terahertz traveling waves and plasmonics. Excited along with a metal grating, the spoof surface plasmons (SSPs) are employed as one of the illuminating sources. When the scattering waves with the SSPs illumination are captured, the sample's high-order spatial frequencies (SF) components are already encoded into the obtainable low-order ones. Then, a modified post-processing algorithm is exploited to shift the modulated SF components to their actual positions in the SF domain. In this manner, the fine information of samples is introduced to reconstruct the desired imaging, leading to an enhancement of the resolution up to 0.12λ0. Encouragingly, the resolution can be further enhanced by attaching extra illumination of SSPs with an elaborately selected frequency. This method holds promise for some important applications in terahertz non-fluorescent microscopy and sample detection with weak scattering.

The upregulated expression of RFC4 and GMPS mediated by DNA copy number alteration is associated with the early diagnosis and immune escape of ESCC based on a bioinformatic analysis.

Esophageal squamous cell carcinoma (ESCC) is a malignant tumor that commonly occurs worldwide. Usually, Asia, especially China, has a high incidence of esophageal cancer. ESCC often has a poor outcome because of a late diagnosis and lack of effective treatments. To build foundations for the early diagnosis and treatment of ESCC, we used the gene expression datasets GSE20347 and GSE17351 from the GEO database and a private dataset to uncover differentially expressed genes (DEGs) and key genes in ESCC. Notably, we found that replication factor C subunit 4 (RFC4) and guanine monophosphate synthase (GMPS) were upregulated but have been rarely studied in ESCC. In particular, to the best of our knowledge, our study is the first to explore GMPS and ESCC. Furthermore, we found that high levels of RFC4 and GMPS expression may result from an increase in DNA copy number alterations. Furthermore, RFC4 and GMPS were both upregulated in the early stage and early nodal metastases of esophageal carcinoma. The expression of RFC4 was strongly correlated with GMPS. In addition, we explored the relationship between RFC4 and GMPS expression and tumor-infiltrating immune cells (TILs) in esophageal carcinoma. The results showed that the levels of RFC4 and GMPS increased with a decrease in some tumor-infiltrating cells. Upregulated RFC4 and GMPS with high TILs indicate a worse prognosis. In summary, our study shows that RFC4 and GMPS have potential as biomarkers for the early diagnosis of ESCC and may played a crucial role in the process of tumor immunity in ESCC.

Terahertz subwavelength edge detection based on dispersion-induced plasmons.

Terahertz imaging has recently attracted great attention owing to the abilities of high penetration and low ionizing damages. However, the low resolution and low contrast resulting from the diffraction limit and unwanted background illumination significantly hinder the extensive usage. In this Letter, we propose and numerically demonstrate a terahertz subwavelength imaging method capable of extracting only the edges and fine features of the targets. The underlying physics is the efficient transmission of the scattering evanescent waves related to key geometric information while blocking the propagating components. By exploiting the structurally induced plasmons in a bounded metallic waveguide, the transmission channel for evanescent waves is realized by hyperbolic metamaterials through periodically stacking dielectric layers. On this basis, high-contrast edge detection with a resolution up to ${0.1}\lambda$ is demonstrated at terahertz wavelengths. The proposed terahertz imaging method may find important applications in non-destructive testing, weak scattering object detection, and high-contrast microscopy.

Bifunctional Luneburg-fish-eye lens based on the manipulation of spoof surface plasmons.

Manipulation of spoof surface plasmons (SSPs) has recently intrigued enormous interest due to the capability of guiding waves with subwavelength footsteps. However, most of the previous studies, manifested for a single functionality, are not suitable for multifunctional integrated devices. Herein, a bifunctional Luneburg-fish-eye lens is proposed based on a 2D metal pillar array. First, by tuning the dimension of the metal pillars in the array, its ability to precisely manipulate the SSPs along one direction is confirmed, achieving subwavelength focusing and imaging with a resolution up to 0.14λ. Then, separately controlling the propagation of the SSPs along the orthotropic directions is further implemented, and the bifunctional Luneburg-fish-eye lens is realized. It is experimentally characterized as a Luneburg lens along the x axis, whereas in the y axis, it presents the properties of a Maxwell fish-eye lens. This bifunctional lens can reduce the system complexity and exert flexibility in multifunctional applications, while the proposed metal pillar-based design method broadens the application range of the gradient refractive-index lens in microwave, terahertz, and even optical ranges.

AKR1C2 acts as a targetable oncogene in esophageal squamous cell carcinoma via activating PI3K/AKT signaling pathway.

The aldo-keto reductases family 1 member C2 (AKR1C2) has critical roles in the tumorigenesis and progression of malignant tumours. However, it was also discovered to have ambiguous functions in multiple cancers and till present, its clinical significance and molecular mechanism in oesophageal squamous cell carcinoma (ESCC) has been unclear. The aim of this study was to explore the role of AKR1C2 in the tumorigenesis of ESCC. Here, we showed that AKR1C2 expression was found to be up-regulated in ESCC tissues and was significantly associated with pathological stage, lymph node metastasis and worse outcomes. Functional assays demonstrated that an ectopic expression of AKR1C2 in ESCC cells resulted in increased proliferation, migration and cisplatin resistance, while knockdown led to inversing effects. Bioinformation analyses and mechanistic studies demonstrated that AKR1C2 activated the PI3K/AKT signalling pathway, furthermore, the inhibitor of PI3K or the selective inhibitor of AKR1C2 enzyme activity could reverse the aggressiveness and showed synergistic antitumour effect when combined with cisplatin, both in vitro and in vivo. In conclusion, Our findings revealed that AKR1C2 could function as an oncogene by activating the PI3K/AKT pathway, as a novel prognostic biomarker and/or as a potential therapeutic target to ESCC.

Free-electron-driven beam-scanning terahertz radiation.

A beam-scanning terahertz (THz) radiation mechanism in a free-electron-driven grating system is proposed for THz applications. By loading a period-asynchronous rod array above the grating, the spoof surface plasmon (SSP) originally excited by the electron changes its radiation characteristics owing to the rod-induced Brillouin zone folding effect. The rod array functions as an antenna and converts the SSP into a spatial coherent THz radiation. The radiation frequency and direction can be precisely controlled by the electron energy. The field intensity of the radiation is increased approximately 20 times compared with that of the conventional Smith-Purcell radiation in the same frequency range. In addition, a microwave-band scaling prototype is fabricated and the frequency-controlled radiation is measured. Excellent agreement between the experimental and simulated results is obtained. This study paves the way for the development of on-chip THz sources for advanced communication and detection applications.

Candidate tumor suppressor gene IRF6 is involved in human breast cancer pathogenesis via modulating PI3K-regulatory subunit PIK3R2 expression.

Background/Aims: The tumor-suppressive functions of interferon regulatory factor 6 (IRF6) in some tumors have been preliminarily established, but its pathogenesis and underlying molecular mechanisms in breast cancer, the most common malignancy in women, remains poorly understood. Methods: Pairs of typical breast cancer cell lines (high- and low-aggressive) in addition to 27 breast cancer tissue samples and 31 non-cancerous breast tissues were used to investigate the expression level of IRF6 and Lentivirus-mediated gain-of-function studies, short hairpin RNA-mediated loss-of-function studies in vivo and in vitro were used to validate the role of IRF6 in breast cancer. Next, we performed RNA-Seq analysis to identify the molecular mechanisms of IRF6 involved in breast cancer progression. Results: Our findings showed that IRF6 was downregulated in highly invasive breast cancer cell lines but upregulated in poorly aggressive ones. Functional assays revealed that elevated IRF6 expression could suppress cell proliferation and tumorigenicity, and enhanced cellular chemotherapeutic sensitivity. To identify the molecular mechanisms involved, we performed a genome-wide and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis in breast cancer cells using RNA sequencing of gene expression profiles following the overexpression of IRF6. Genome-wide and KEGG analyses showed that IRF6 might mediate the PI3K-regulatory subunit PIK3R2, which in turn modulated the PI3K/AKT pathway to control breast cancer pathogenesis. Conclusion: We provide the first evidence of the involvement of IRF6 in breast cancer pathogenesis, which was found to modulate the PI3K/AKT pathway via mediating PIK3R2; indicating that IRF6 can be targeted as a potential therapeutic treatment of breast cancer.

High-efficiency directional excitation of spoof surface plasmons by periodic scattering cylinders.

In this Letter, we propose and experimentally demonstrate a simple but efficient method to excite spoof surface plasmons (SSP) through periodic metallic cylinders at microwave frequencies. The rigorous multiple scattering theory indicates that most of the incident propagating waves can pass the cylinders and be converted into the desired harmonics. Furthermore, by tuning the incident angle, controlling the directions of the excited SSP at different frequencies is also realized. The numerical simulations achieve a bidirectional efficiency of 90% at 9.68 GHz and unidirectional efficiency of 79%-85% at 7.46-9.7 GHz, when the incident angle changes from 60° to 120°. Meanwhile, the maximum contrast ratio between the powers of SSP launched in two opposite directions can reach up to 34 dB. The experimental results under 90° and 77.5° illuminations at 9.68 and 8.56 GHz provide strong support for the coupling mechanism. This method may provide technique support in the SSP-based communication and imaging systems.

High-efficiency terahertz spin-decoupled meta-coupler for spoof surface plasmon excitation and beam steering.

Spoof surface plasmon (SSP) meta-couplers that efficiently integrate other diversified functionalities into a single ultrathin device are highly desirable in the modern microwave and terahertz fields. However, the diversified functionalities, to the best of our knowledge, have not been applied to circular polarization meta-couplers because of the spin coupling between the orthogonal incident waves. In this paper, we propose and demonstrate a terahertz spin-decoupled bifunctional meta-coupler for SSP excitation and beam steering. The designed meta-coupler is composed of a coupling metasurface and a propagating metasurface. The former aims at realizing anomalous reflection or converting the incident waves into SSP under the illumination of the right or left circular polarization waves, respectively, and the latter are used to guide out the excited SSP. The respective converting efficiency can reach 82% and 70% at 0.3THz for the right and left circular polarization incident waves. Besides, by appropriately adjusting the reflection phase distribution, many other functionalities can also be integrated into the meta-coupler. Our study may open up new routes for polarization-related SSP couplers, detectors, and other practical terahertz devices.

Terahertz multichannel metasurfaces with sparse unit cells.

Reflective multichannel metasurfaces are flat reflectors that can control incident and reflected waves in a number of propagating directions simultaneously. However, they are always densely discretized with a high spatial resolution, which increases the manufacturing complexity. In this Letter, to the best of our knowledge, a new method that combines the array antenna theory with the metagratings theory is proposed. We demonstrate that the unit cells with a linear gradient phase in each period of the metasurfaces can eliminate specific space harmonics. With this method, multichannel metasurfaces can be designed with sparse unit cells, and high efficiency is maintained simultaneously. As proofs of the method, we design three different terahertz multichannel metasurfaces with no more than three unit cells per period. The simplification of structures can efficiently reduce the manufacturing complexity. This work may open up new routes in designing multichannel metasurfaces.

GTSE1 is involved in breast cancer progression in p53 mutation-dependent manner.

BACKGROUND: With the rapid development of the high throughput detection techniques, tumor-related Omics data has become an important source for studying the mechanism of tumor progression including breast cancer, one of the major malignancies worldwide. A previous study has shown that the G2 and S phase-expressed-1 (GTSE1) can act as an oncogene in several human cancers. However, its functional roles in breast cancer remain elusive. METHOD: In this study, we analyzed breast cancer data downloaded from The Cancer Genome Atlas (TCGA) databases and other online database including the Oncomine, bc-GenExMiner and PROGgeneV2 database to identify the molecules contributing to the progression of breast cancer. The GTSE1 expression levels were investigated using qRT-PCR, immunoblotting and IHC. The biological function of GTSE1 in the growth, migration and invasion of breast cancer was examined in MDA-MB-231, MDA-MB-468 and MCF7 cell lines. The in vitro cell proliferative, migratory and invasive abilities were evaluated by MTS, colony formation and transwell assay, respectively. The role of GTSE1 in the growth and metastasis of breast cancer were revealed by in vivo investigation using BALB/c nude mice. RESULTS: We showed that the expression level of GTSE1 was upregulated in breast cancer specimens and cell lines, especially in triple negative breast cancer (TNBC) and p53 mutated breast cancer cell lines. Importantly, high GTSE1 expression was positively correlated with histological grade and poor survival. We demonstrated that GTSE1 could promote breast cancer cell growth by activating the AKT pathway and enhance metastasis by regulating the Epithelial-Mesenchymal transition (EMT) pathway. Furthermore, it could cause multidrug resistance in breast cancer cells. Interestingly, we found that GTSE1 could regulate the p53 function to alter the cell cycle distribution dependent on the mutation state of p53. CONCLUSION: Our results reveal that GTSE1 played a key role in the progression of breast cancer, indicating that GTSE1 could serve as a novel biomarker to aid in the assessment of the prognosis of breast cancer.

p53, latent membrane protein 1, bcl-2, and prognosis in nasopharyngeal carcinoma: a meta-analysis.

The controversy of (p53) in nasopharyngeal carcinoma persists, despite the fact that many studies have been conducted on its correlation with latent membrane protein 1 (LMP1), bcl-2, and prognosis. To better understand this postulated relationship, a meta-analysis was performed based on existing relevant studies. A total of 19 individual studies with a total of 1189 patients were included in the meta-analysis. Overall, the results revealed a significant association of p53-positive status with a poor 5-year survival of nasopharyngeal carcinoma (NPC) patients as the risk difference (RD) was -0.17 (95% CI, -0.31, -0.03; P=0.02, Pheterogeneity =0.01).The overall odds ratio (OR) for LMP1 in the p53 positive group vs. negative group revealed that a significantly elevated risk of positive LMP1 in the former was achieved (OR 5.52 95% CI, 2.66-11.46; P<0.00001, Pheterogeneity =0.78). Similarly, a strong correlation between bcl-2 and p53 was found with an OR 6.85 (95% CI, 2.37-19.74; P=0.0004, Pheterogeneity =0.48). However, there did not appear to be any correlations with clinical parameters such as gender, tumor site, lymph node metastasis,pathological type and TNM stage. In conclusion, p53 expression is related to the survival of nasopharyngeal carcinoma. It can be considered as the auxiliary detection index in treatment and prognosis of nasopharyngeal carcinoma.

Superfocusing of terahertz wave through spoof surface plasmons.

In this paper, we propose and numerically demonstrate a new way to realize superfocusing of terahertz waves via the spoof surface plasmons (SSP). With the assist of a modified subwavelength metallic grating, a near-field rapid oscillation can be formed, originating from the Fabry-Perot resonances due to the reflection of SSP waves at terminations. We show that the field pattern of oscillation on textured metallic surface can be engineered by adjusting groove width and grating number. This produces a desired modulation of phase and amplitude for the radiationless electromagnetic interference (REI) focusing. The effective focusing depth through the corrugated metal is evaluated by the full-width-half-maximum (FWHM) beamwidth. At the situation of third-order Fabry-Perot resonance, the FWMH reaches up to 0.069λ at a distance of 0.1λ, improving the beamwidth by more than 540% compared with a single slit. The FWHM is optimized to 0.06λ as the order of Fabry-Perot resonance becomes seven, leading to the superfocusing metric of 1.67. On the basis of this, we further show the focusing ability can be held on the ultra-thin metallic grating. Two-dimensional subwavelength focusing behavior is also numerically verified. Our study may extend the working distance of sensing and super-resolution imaging devices at terahertz frequency.

Experimental demonstration of an ultra-broadband subwavelength resolution probe from microwave to terahertz regime.

An ultra-broadband subwavelength resolution probe that consists of a Teflon rod and six metallic strips is developed for the near-field imaging system. The slit between two metallic strips maintains quasi-TEM modes, avoiding the problem of low coupling efficiency caused by the cutoff effect. The numerical calculations visualize the process of energy compression into a 0.047λ diameter spot with great field enhancement at the taper apex, and the probe holds subwavelength focusing behavior from 10 GHz to 0.25 THz. Although limited by the fabrication, the resolution of 0.16 and 0.25λ are still experimentally demonstrated at 14 GHz and 0.1 THz. The properties of easy fabrication and no cutoff frequency would lower the threshold of a high-resolution near-field imaging system.

Terahertz super-resolution imaging using four-wave mixing in graphene.

A perfect lens made from negative refraction (NR) materials is utilized to overcome the diffraction limit. However, these NR lenses are realized by metamaterials, which suffer from high losses, and the volume is bulky. In this Letter, we propose a terahertz NR lens by using a four-wave mixing (FWM) process in graphene. NR is demonstrated because of the phase matching along the surface of graphene. Evanescent waves that store high spatial frequency information can be converted into propagating waves in the nonlinear NR process. An image with subwavelength resolution is reconstructed at the FWM wavelength. Theoretical analysis and numerical simulations are performed to demonstrate the capability of such imaging. The lens has a subwavelength resolution of around λ/5. The lens needs low field intensity due to the strong nonlinear response of graphene in the terahertz frequency. This Letter may have applications in terahertz microscopy.

The developmental transcription factor IRF6 attenuates ABCG2 gene expression and distinctively reverses stemness phenotype in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC), which originates from the nasopharynx, is highly prevalent in Southern China and Southeast Asia, and more than 90% of all NPCs are non-keratinizing undifferentiated cells or poorly differentiated squamous cells. Cancer stem cells (CSCs) are capable of self-renewal and have differentiation potential. These properties form the basis of cancer initiation, development, and radiochemoresistance. However, the molecular mechanisms underlying NPC CSC maintenance remain poorly understood. Here, genomic expression profiling using our previously established monoclonal cellular and animal models revealed that interferon regulatory factor 6 (IRF6) was downregulated in highly metastatic NPC cells, cancer stem-like NPC cells and animal models. Functional assays revealed that elevated IRF6 expression suppressed cell proliferation, growth, CSCs properties and enhanced cell chemotherapeutic sensitivity. However, silencing IRF6 resulted in opposing effects. Moreover, we determined that as a tumor suppressor gene and transcription factor, IRF6 directly bound the upstream region of the ATP-binding cassette sub-family G member 2 (ABCG2) DNA element and suppressed target ABCG2 expression in NPC cells. Consistently, an inverse correlation was observed between the mRNA levels of IRF6 and ABCG2 in clinical NPC samples. With these results, we provide the first evidence that IRF6 directly targets the ABCG2 gene and selectively kills CSCs in NPC and that IRF6 may be a valuable tool for developing new CSC-targeted treatment strategies for undifferentiated NPC patients.

Tunable Terahertz Deep Subwavelength Imaging Based on a Graphene Monolayer.

The resolution of conventional terahertz (THz) imaging techniques is limited to about half wavelength, which is not fine enough for applications of biomedical sensing and nondestructive testing. To improve the resolution, a new superlens, constructed by a monolayer graphene sheet combining with a grating voltage gate, are proposed in this paper to achieve deep super-resolution imaging in the THz frequency range. The main idea is based on the Fabry-Perot resonance of graphene edge plasmon waves. By shaping the voltage gate into a radial pattern, magnified images of subwavelength targets can be obtained. With this approach, the finest resolution can achieve up to λ/150. Besides, the superlens can be conveniently tuned to work in a large frequency band ranging from 4.3 THz to 9 THz. The proposal could find potential applications in THz near-field imaging systems.