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Nowadays, cancer and cardiac diseases are two of the most causes of death, so cancer treatment-related cardiac death cannot be ignored. For lung cancer, chest radiotherapy (RT) is essential, but the related cardiotoxicity has not been fully studied.We reviewed the data of 11,455 patients with non-small cell lung cancer (NSCLC) from the Surveillance, Epidemiology, and End Results database from 2001 to 2015. The change trend for concomitant cardiovascular diseases (CVD)-specific death was calculated and graphically demonstrated. Univariate and multivariate analyses for survival were performed using Cox risk regression model.In our analysis, the overall incidence and mortality from NSCLC declined, but CVD-specific death increased. Both chemoradiotherapy and radiotherapy alone played a significant role in CVD-specific death. Analyzed longitudinally from diagnosis, we found that the effect of RT in CVD-specific death increased continuously over the third years and the hazard ratio for CVD-specific death was 1.386 times between RT and non-RT group (HR = 1.386, 95% CI 1.322-1.452; p 0.0001). On the other hand, RT played a protective role in CVD-specific death before the second years, especially in recent years from 2013 to 2015 (HR = 0.843, 95% CI 0.740-0.959; p = 0.009).Although the mortality from NSCLC decreased, but radiotherapy-related CVD-specific mortality cannot be ignored. In the long-term over 3 years, RT significantly promoted CVD-specific death. However, RT turned to be a protective role in the short-term within 2 years. In clinical practice, we need to comprehensively consider the dual effects of radiotherapy on the side effect of heart.

Lung cancer has become a global health issue in recent decades. Approximately 80-85% of cases are non-small-cell lung cancer (NSCLC). Despite the high rate of resistance, cisplatin-base chemotherapy is still the main treatment for NSCLC patients. Thus, overcoming cisplatin resistance is urgently needed in NSCLC therapy. In this study, we identify NADPH metabolism and reactive oxygen species (ROS) levels as the main causes accounting for cisplatin resistance. Based on a small panel consisting of common chemotherapy drugs or compounds, APR-246 is proved to be an effective compound targeting cisplatin-resistant NSCLC cells. APR-246 specially inhibits proliferation and colony formation of cisplatin-resistant cells. In details, APR-246 can significantly cause G0/G1 accumulation and S phase arrest of cisplatin resistant cells and gives rise to severe mitochondria dysfunction as well as elevated apoptosis. Further study proves that it is the aberrant ROS levels as well as NRF2/SLC7A11/GSH axis dysfunction accounting for the specific antitumor effects of APR-246. Scavenging ROS with N-acetylcysteine (NAC) disrupts the inhibitory effect of APR-246 on cisplatin-resistant cells. Mechanistically, NRF2 is specifically degraded by the proteasome following its own ubiquitylation in APR-246-treated cisplatin-resistant cells, which in turn decreases NRF2/SLC7A11/GSH axis activity. Our study provides new insights into the biology driving cisplatin resistance of lung cancer and highlights APR-246 as a potential therapeutic reagent for overcoming cisplatin resistance.

Geothermal resources are a clean and renewable energy source that can play a critical role in drastically reducing air pollution. The utilization of geothermal resources requires technical support to decrease the developing risk by applying an integrated interpretation of geophysical methods. In this study, we used geophysical methods in the Langfang region of China to design a workflow for the safe yield of geothermal resources. To do so, we conducted controlled-source audio-frequency magnetotelluric (CSAMT) soundings, shallow soil temperature surveys, radon gas measurements, and the microtremor survey method (MSM) at the geothermal exploration and development site. These geophysical analyses identified a geothermal reservoir and a buried channel in the region. The dominant fault developing in the area was identified as the best channel for heat and water based on the developed geothermal wells. In areas with relatively little geothermal exploration, this study provides a reference and demonstration for geothermal development.

A comprehensive understanding of the internal structure and construction of a geomechanical formation model play an important role in developing and using geothermal resources. Formation models help in identifying the channel and cycling modes of the heat flow. Due to urban sprawl and development, constructing a formation model of geothermal resources based on data from traditional geophysical methods is challenging. The microtremor survey method (MSM) is adopted to obtain critical information in Jimo, which is famous for rare seawater geothermal resources in China. Three microtremor survey lines are deployed to identify subsurface structures up to 2 km into the ground. Dispersion curves of Rayleigh waves with frequencies from 0.4 to 10 Hz are extracted using the spatial autocorrelation method. An empirical equation is adopted to obtain the apparent shear wave (S-wave) velocity of each survey point and to plot the apparent S-wave velocity sections. The obtained sections reveal the development of two interacting faults, which form a channel for the heat-flow cycle. Two conceptual models are established to depict the formation and cycling modes of seawater geothermal resources in Jimo, based on the results and analysis. Our model will help verify the geothermal system and scientifically guide the development of unique geothermal resources. Moreover, the developed model verifies that MSM is effective and dependable for identifying fracture zones and strata.

Esophageal squamous cell carcinoma (ESCC) is one of the most common gastrointestinal tumors, accounting for almost half a million deaths per year. Cancer-associated fibroblasts (CAFs) are the major constituent of the tumor microenvironment (TME) and dramatically impact ESCC progression. Recent evidence suggests that exosomes derived from CAFs are able to transmit regulating signals and promote ESCC development. In this study, we compared different the component ratios of miRNAs in exosomes secreted by CAFs in tumors and with those from normal fibroblasts (NFs) in precancerous tissues. The mRNA level of hsa-miR-3656 was significantly upregulated in the former exosomes. Subsequently, by comparing tumor cell development in vitro and in vivo, we found that the proliferation, migration and invasion capabilities of ESCC cells were significantly improved when miR-3656 was present. Further target gene analysis confirmed ACAP2 was a target gene regulated by miR-3656 and exhibited a negative regulatory effect on tumor proliferation. Additionally, the downregulation of ACAP2 triggered by exosomal-derived miR-3656 further promotes the activation of the PI3K/AKT and β-catenin signaling pathways and ultimately improves the growth of ESCC cells both in vitro and in xenograft models. These results may represent a potential therapeutic target for ESCC and provide a new basis for clinical treatment plans.

Esophageal cancer is a complex malignancy and the sixth leading cause of cancer death worldwide. In Eastern Asia including China, about 90% of all incident cases have esophageal squamous cell carcinoma (ESCC). Mounting evidence elucidates that aberrant expression of various non-coding RNAs (ncRNAs) contributes to ESCC progression, but it remains unclear how small nucleolar RNAs (snoRNAs) are involved in ESCC development. We systemically screened clinically relevant snoRNAs in ESCC via integrative analyses of The Cancer Genome Atlas (TCGA) data and validation in ESCC tissues. We found that snoRNA SNORD12B was one of the most evidently upregulated snoRNAs in ESCC specimens and its high expression was significantly associated with poor prognosis of patients. SNORD12B profoundly promoted proliferation, migration, invasion, and metastasis of ESCC cells in vitro and in vivo, indicating its oncogene nature. In particular, SNORD12B could interact with PP-1α, one of the three catalytic subunits of serine/threonine protein phosphatase 1, which is a major phosphatase that directly dephosphorylates AKT to suppress its activation. Interestingly, high levels of SNORD12B in ESCC cells could break interactions between 14-3-3ζ and PP-1α, abolish the retention of PP-1α in the cytosol by 14-3-3ζ and relocate PP-1α from the cytosol to the nucleus. This led to sequestered PP-1α in the nucleus, enhanced phosphorylation of AKT in the cytosol, activated AKT-mTOR-4EBP1 signaling, and, thus, ESCC progression. These insights would improve our understanding of how snoRNAs contribute to tumorigenesis and highlight the potential of snoRNAs as future therapeutic targets against cancers.

S-wave velocity and thickness of weathered strata are the important parameters to engineering construction. In this study, array measurements of microtremors were carried out at 50 sites in Jimo, China. It revised the observation array that a small scale array was placed in the center of traditional regular triangle observation array. The field data of Jimo verified that it is effective to identify the different degrees of weathered strata above fresh bedrock. Based on the spatial autocorrelation (SPAC) method, the dispersion curves were achieved. While the S-wave velocity structure was estimated using the fork genetic algorithm. By using small scale observation array, it identifies different strata including weathered layer in detail. In order to test the accuracy of inversion results, 5 sites were chosen to drill. Comparison between inversion results and boreholes, it shows agreement with logs data. At last, the S-wave velocity structures in different depths above the fresh bedrock were plotted. We delineated the S-wave velocity structure for the first time in this research region using revised measurement of microtremors signal. The depth of fresh bedrock fluctuates strongly which is affected by weathered. This method provides another means to distinguish the degree of weathered, depth of fresh bedrock, and S-wave velocity structure of shallow strata.

Assessment of available heat capacity in the shallow ground is important to the development of ground source or geothermal heat pumps. A new volumetric method-based approach is proposed for evaluating shallow geothermal potential by combining microtremor survey results. Parameters such as thickness of clay and sandy gravel layers can be achieved by processing the microtremor filed data. The study area was divided into grids based on the different exploration sites. The heat present in each small unit was calculated using the revised volumetric method. This division into small units improved the accuracy of assessment of the geothermal potential and helped plot the distribution map of the available heat amount, which indicated optimal locations for development and utilization of shallow geothermal resources. Jimo, China was used as an example to depict the calculation flow. Since the microtremor survey method can identify the thickness of clay, sandy gravel, and fresh bedrock layers in shallow ground, the amount of shallow geothermal resources present above fresh bedrock was calculated. In Jimo, the amount of exploitable geothermal resources, using the traditional volumetric method, was found to be 4.92 × 1012 kJ. The proposed calculation method not only provided a higher corresponding value of 6.96 × 1012 kJ but also showed the regions with the highest potential of shallow geothermal resources. Hence, this approach provides an alternative method for geothermal potential assessment which can be used globally.

High-resolution imaging has become more popular recently in exploration geophysics. Conventionally, geophysicists image the subsurface using the isotropy approximation. When considering the anisotropy effects, one can expect to obtain an imaging profile with higher accuracy than the isotropy approach allows. Orthorhombic anisotropy is considered an ideal approximation in the realistic case. It has been used in the industry for several years. Although being attractive, broad application of orthorhombic anisotropy has many problems to solve. We have developed a novel approach of prestack time migration in the orthorhombic case. The traveltime and amplitude of a wave propagating in orthorhombic media are calculated directly by launching new anisotropic velocity and anisotropic parameters. We validate our methods with synthetic data. We also highlight our methods with model data set and real data. The results found that our methods work well for prestack time migration in orthorhombic media.

To explore and utilize the urban underground space, it is important for us to accurately obtain information on the near surface structures. Microtremor signals play a vital role in that they carry abundant information about the subsurface structure and can be easily observed under disturbance of human activities in urban areas. We collected microtremor signals at 24 sites along a survey line in central Jinan city, obtained the dispersion curves by using the Extended Spatial Autocorrelation method and the resonance frequencies by using the horizontal-to-vertical spectral ratio method, and inverted the near surface structures by using the forking genetic algorithm. The lateral variation of the soil–rock interface was delineated at a maximum depth of 33 m and a large fracture zone was determined at a width of approximately 300 m. The frequency peaks changed from 2.5 to 7.3 Hz for the fracture and stable zones. A frequency-dependent model of the sediment thickness was obtained as $h = 101{f_r}^{ - 1.13}$, where h is the depth with a unit of m and fr is the resonance frequency. These results may be useful for understanding near surface structures and then benefit exploration of urban underground space.

BackgroundLung cancer has become a global health issue in recent decades. Despite of high rate of resistance, cisplatin-base chemotherapy is still the main treatment of lung cancer patients who are not suitable for TKI-based targeted therapy and immunotherapy. Thus, overcoming cisplatin resistance is urgently needed.MethodsA small panel is established to screen chemicals and compounds overcoming cisplatin resistance. Survival fractions as well as proliferation are determined by MTT assay. Colony formation assay, JC-1 assay, EdU assay, ROS assay as well as apoptosis and cell cycle assay are performed to verify vitalities of different groups. Quantifications of NADP+/NADPH and GSH/GSSG are carried out according to standard protocols. Xenograft model is generated to evaluate the in vivo role of APR-246.ResultsIn this study, we identify NADPH metabolism and reactive oxygen species (ROS) levels as the main cause accounting for cisplatin resistance of H460. Based on a small panel consisting common chemotherapy drugs and compounds, APR-246 is proved an effective compound specifically inhibiting proliferation and colony formation of cisplatin resistant H460 (H460-Cis) cells. APR-246 significantly causes G0/G1 accumulation and S phase inhibition of H460-Cis cells. Besides, APR-246 can obviously lead to severe mitochondria dysfunction as well as elevated apoptosis by altering apoptosis-related protein expressions in H460-Cis cells. Further study proves that it is the aberrant ROS levels as well as NRF2/SLC7A11/GSH axis dysfunction accounting for the specific anti-tumor effects of APR-246. Mechanistically, NRF2 is specifically ubiquitylated degraded in APR-246 treated H460-Cis cells, which in turn decrease NRF2/SLC7A11/GSH axis activity.ConclusionOur study uncovered new insights into the biology driving cisplatin resistance of lung cancer and highlights potentials of APR-246 as future therapeutic agents again cisplatin resistance.

Photothermal therapy (PTT), mediated by tumor-targeted drug delivery of indocyanine green (ICG), is a promising strategy for cancer therapy. Human epidermal growth factor receptor 3 (Her3) is highly expressed in several solid tumors and is an ideal target for tumor diagnosis and therapy. This study prepared a Her3-specific dimeric affibody (Z

Fibroblast growth factors (FGFs) and their receptors (FGFRs) modulate a wide range of biological functions, especially tumor genesis. The aim of this study was to investigate the possible association of FGFR expression with the susceptibility of digestive system and reproductive system cancers in Chinese population. In total, 343 patients with digestive or reproductive system cancers were enrolled in this study. The expression levels of four highly-conserved FGFRs including FGFR1, FGFR2, FGFR3 and FGFR4 were measured by immunohistochemistry (IHC). The expression levels of FGFRs were compared between carcinoma and para-carcinoma tissues. FGFR1 expression significantly differed between carcinoma and para-carcinoma tissues in colon and gastric cancers. FGFR2 expression significantly differed between carcinoma and para-carcinoma tissues in esophageal cancer. FGFR3 expression was significantly different between carcinoma and para-carcinoma tissues in liver and gastric cancers. FGFR2 showed the highest expression probability in all the selected cancers and FGFR4 showed the lowest expression probability. FGFR1 and FGFR3 showed comparable moderate expression probabilities. Our findings have demonstrated significant differences regarding FGFR expression levels between carcinoma and para-carcinoma cells in digestive or reproductive system cancer patients. The data also implicated that FGFR2 and FGFR4 could serve as two prominent factors closely related to the susceptibility of digestive and reproductive system cancers.

Cancer-associated fibroblasts (CAFs) are believed to influence tumor behavior and clinical outcomes. We previously showed that conditioned medium (CM) from CAFs induces proliferation and motility of esophageal squamous cell carcinoma (ESCC) cells. Here, we investigated the molecular mechanisms by which the CAF-secreted proteins induce ESCC development and progression. Using antibody arrays, we identified urokinase plasminogen activator (uPA) as one of the main proteins whose release was increased in CAFs compared to normal fibroblasts (NFs). Immunohistochemical analysis of pathological sections showed that uPA-positive cells were localized at the boundaries of tumor and stroma tissues, in stroma between tumor nests, and within the tumors. Increased stromal uPA levels (132/146 cases) correlated with tumor invasion (p < 0.05) and overall survival of ESCC patients (p < 0.05). In vitro assays showed that uPA promotes ESCC cell proliferation, migration, and invasion via PI3K/AKT and ERK signaling pathways. In vivo, anti-uPA antibody suppressed tumor growth in ESCC xenografts. These results suggest that uPA released from stroma, and especially from CAFs, might be a predictive marker for ESCC diagnosis and prognosis, as well as an effective therapeutic target.

Thermal conductivity is an important physical property of geological formations. For example, a comprehensive assessment of the thermal conductivity variations in the shallow ground surrounding a heat exchanger borehole can be used to determine the installation parameters of a ground-source heat pump. However, in some locations, it is not possible to measure thermal conductivity directly. One of the most common methods to indirectly infer thermal conductivity is to establish correlations between thermal conductivity and various geophysical parameters. By utilising test data acquired from drilling sites and ascertaining the corresponding geophysical parameters via non-invasive geophysical methods, such correlations can be obtained. At 11 test sites, the thermal conductivities were measured in situ via thermal response testing, and the corresponding values for the S-wave velocity and density were calculated using the Microtremor survey method (MSM). The correlations between the thermal conductivity, S-wave velocity, and density in the tested shallow ground were built by exponential fitting. By utilising the established correlations, two-dimensional (2D) cross-sections along the microtremor survey line were created to illustrate the thermal conductivity variations in the shallow ground. These results demonstrate that this approach can be used to infer the thermal conductivities of areas that cannot be tested directly.

Esophageal cancer is the eighth most common malignant tumor worldwide, of which esophageal squamous cell carcinoma (ESCC) is the dominant histological subtype. A drug shortage for ESCC therapy triggered us to explore the roles of fibroblast growth factor receptor 2 (FGFR2) and its upstream regulator miR-671-5p in ESCC progression. We compared the levels of FGFR2 and miR-671-5p between human ESCC tissues and their matched normal esophageal tissues and found an association between higher levels of FGFR2 and lower levels of miR-671-5p in ESCC tissues. High levels of FGFR2 resulted in the activation of the ERK and AKT pathways and a promotion of ESCC progression. High levels of miR-671-5p specifically reduced the expression of FGFR2 and suppressed ESCC progression in both in vitro and in vivo models. Therefore, suppressing FGFR2 and enhancing miR-671-5p expression may be the right approaches for ESCC therapy.

The current study aimed to explore the functions and roles of microRNA-193b (miR-193b) in the myocardium with ischemia-reperfusion (I/R) injury and a potential therapeutic method for myocardial I/R injury. The mice were subjected to myocardial I/R with or without miR-193b pretreatment. The infarct size and myocardial enzymes were detected. The terminal deoxynucleotidyl transferase dUTP nick-end labeling assay was conducted to investigate the effect of miR-193b on cardiomyocyte apoptosis. The expression levels of miR-193b and mastermind-like 1 (MAML1) were validated by quantitative real-time polymerase chain reaction and Western blot analysis. The results suggested that the miR-193b expression level was significantly downregulated in the myocardium with I/R injury compared with control group. miR-193b overexpression is able to reduce infarct size and myocardial enzymes after myocardial I/R injury. Furthermore, overexpression of miR-193b could alleviate the apoptosis level after myocardial I/R injury. Taken together, the present study demonstrated that upregulated miRNA-193b alleviated myocardial I/R injury via targeting MAML1.

For the sake of safety, it is crucial for civil engineers to determine the thickness of the sediment layers in the urban areas. However, the noisy detection environment in a city presents a significant challenge to the traditional artificial source geophysical methods which are used to estimate and monitor of sediment thickness. Given this otherwise challenging detection environment, the H/V spectral ratio method provides an effective and cheap means of detecting sediment thickness. It exploits microtremor signals to obtain the resonant frequency of the surface layer which is then used to determine site sediment thickness with an empirical equation using the data from a single observation station. In this study, we collected microtremor data at 109 locations in the Aoshan Bay area of the Shandong Peninsula and determined the resonant frequency and analysed the morphological features of the H/V spectral ratio curves. In order to calibrate the frequency-bedrock depth equation accurately to the local conditions, Vs profile estimation is used to fine tune the frequency-bedrock depth equation. By comparing the S-wave velocity structure obtained using the microtremor SPAC method with that found from borehole samples, we were able to verify the reliability and accuracy of application of the microtremor SPAC method. By using the H/V spectral ratio method and the modified equation that transforms resonance frequencies to sediment thickness, we generated a thickness map of the sedimentary layers in the Aoshan Bay area of the Shandong Peninsula. The map provides useful information for ensuring the safe construction of the city's infrastructure. We conclude that the use of microtremor signals can provide important geological information as a cheaper and quick way for the construction and development of urban infrastructure.

Background: Exosome plays an important role in cell communication and cell environment. But the mechanism of how exosome derived from cancer-associated fibroblast (CAF) influent esophageal squamous cell carcinoma (ESCC) progression is not clear. In this work, compared with normal fibroblast-derived exosomes (NDEs), we found that CAF derived exosomes (CDEs) can enhance the growth, migration, and invasion of ESCC cells obviously. Therefore, we would like to clarify the role of CDEs in ESCC progression. Methods and Results: Using microRNA array to analyze the different miRNAs in the CDEs and NDEs, we got a series of up-regulation miRNAs and two down-regulation miRNAs in CDEs. Among them, miR-3656 shows a significantly highest level. Then, we transfected miR-3656 mimics to the ESCC cells and found the mimics increased the growth, migration, and invasion of ESCC cells in cell proliferation assay. cell scratch tests and chamber invasion experiments. We established recombinant ESCC cells with miR-3656 high expression by the lentiviral system. The cells were injected into mice to form the xenograft tumor. The results showed the miR-3656 can enhance the tumor formation. After that, aided by TargetScan software, we found ACAP2, one of miR3656 targets, was significantly down-regulating in ESCC cells at the high level of miR-3656. When ACAP2 expression was knocked-down by siRNA, the proliferation and migration of ESCC cells was increased, which indicated ACAP2 a potential anti-tumor factor. Furthermore, we detected the different proteins between ESCC cells with high expression miR-3656 and normal ESCC cells through LC_MS; the results were analyzed by Integrate Pathway Analysis (IPA) system and many differential proteins were found to be involved of PI3K/AKT and Wnt pathways. Conclusions: In this study, we found the CDEs promote the progression of their sounding ESCC cells in vitro and in vivo. The main reason is that CDEs carry some tumor-promoting miRNAs that influent the target ESCC cells. Especially, miR-3656 expresses the highest level of miRNAs in CDEs. It not only decreases the expression of ACAP2 but also impacts the expression of proteins involved PI3K/AKT and Wnt pathways in ESCC cells. The results indicate the CDEs playing a very important role in ESCC progression. Citation Format: Xiaojia Chen, Yuan Jin, Bihui Zhang, Xiaocen LI, Baoqing Tian, Qiang Wang, An Hong. Exosome from CAF-ESCC aggravates tumor progression by its containing molecular miR-3656 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1987.

Application of geothermal resources draws growing attention in recent years as geothermal resources are an emerging clean and renewable energy. There are tremendous geothermal resources in Jiangsu Province, which have been considered as significant contributions to regional economic development and climate variation. Controlled by tectonic structure, the spatial distribution of geothermal resources is highly uneven. Because of the complexity in terms of thermal storage background and reservoir types, successful application of geothermal resources is facing many practical difficulties such as determining the drilling location of geothermal well; thus, successful geothermal exploration is still of high risk. Firstly, geothermal resources of Jiangsu Province can be categorized into four areas; thus, geothermal reservoirs of different areas are discussed in this paper. According to the results of rock samples testing and analyzing, a geothermal reservoir physical model of Southern Jiangsu geothermal resource area has been established, which can provide an initial restriction for microtremor inversion. Two survey points with major inversion error under “blind inversion” are recalculated as well. The results show that the initial inversion model can effectively improve the accuracy of inversion and thus benefit the sounding reservoirs. By introducing the actual initial inversion model, microtremor survey method can achieve more accurate results to provide critical information for the development of geothermal resources, which reduce the risk of successful geothermal drilling.

Small interfering RNAs (siRNA)/microRNAs (miRNA) have promising therapeutic potential, yet their clinical application has been hampered by the lack of appropriate delivery systems. Herein, we employed extracellular vesicles (EVs) as a targeted delivery system for small RNAs. EVs are cell-derived small vesicles that participate in cell-to-cell communication for protein and RNA delivery. We used the aptamer AS1411-modified EVs for targeted delivery of siRNA/microRNA to breast cancer tissues. Tumor targeting was facilitated via AS1411 binding to nucleolin, which is highly expressed on the surface membrane of breast cancer cells. This delivery vesicle targeted let-7 miRNA delivery to MDA-MB-231 cells in vitro as confirmed with fluorescent microscopic imaging and flow cytometry. Also, intravenously delivered AS1411-EVs loaded with miRNA let-7 labeled with the fluorescent marker, Cy5, selectively targeted tumor tissues in tumor-bearing mice and inhibited tumor growth. Importantly, the modified EVs were well tolerated and showed no evidence of nonspecific side effects or immune response. Thus, the RNAi nanoplatform is versatile and can deliver siRNA or miRNA to breast cancer cells both in vitro and in vivo. Our results suggest that the AS1411-EVs have a great potential as drug delivery vehicles to treat cancers.

Esophageal cancer is the world's tenth common malignant tumor. Esophageal cancer is divided into esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (ECA). ESCC is the dominant histological subtype. The overall 5-year survival rate for people with advanced-stage of ESCC is only about 10%-20%, but ESCC is still not well-studied. Therefore, it is very important to study the mechanism of cancer progression in ESCC in order to develop new therapies for this deadly disease. Fibroblast growth factor receptor2 (FGFR2) is one of the RTK members and generally regarded as an oncogene, but little is known about its function in ESCC. In our study, we proved FGFR2 played the key role in ESCC progression. From In vitro studies, overexpression of FGFR2 promoted the ESCC cells' migration, invasion, and proliferation, which was confirmed through knocking down FGFR2 in ESCC cells. In vivo xenograft tumor mouse model studies showed the tumor size from ESCC cells with FGFR2 over-expression larger than that of the control group. Conversely, the tumor size from ESCC cells with FGFR2 knock-down was significantly smaller compared with the control group. Molecular mechanism studies showed that overexpression of FGFR2 activated the ERK and AKT signal pathways and altered the cell cycle in ESCC. In addition, decreased expression of miR-671-5p was identified by microRNA array and QPCR verify assay in ESCC–FGFR2+ tissue. Using a dual influence report system, we confirmed miR-671-5p could regulate expression of FGFR2. It was also found that FGFR2 was highly expressed whereas miR-671-5p was expressed at a low level in most of the FGFR2-positive ESCC clinic samples. Furthermore, we demonstrated that miR-671-5p could inhibit the proliferation and metastasis of ESCC cells in vitro and it could suppress growth of ESCC in vivo. The miR-671-5p suppressed MAPK and PI3K signal pathways through down-regulation of phosphorylation of FGFR2. Therefore, miR-671-5p was seen as a tumor suppressor in ESCC. Our results demonstrated that FGFR2 and miR-671-5p are potential therapeutic targets in ESCC. They both participate in the progression of ESCC, but also play the contrasting roles. Antagonists of FGFR2 or activators of miR-671-5p could be therapeutics against ESCC. Citation Format: Xiaojia Chen, Xiaoyan Li, Baoqing Tian, Xuan Tan, Wei Han, Jiakang Wang, An Hong. FGFR2 and miR-671-5p as key participants involved in the progression of human esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2520.

The HMGA2 (high-mobility group AT-hook) protein has previously been shown as an oncoprotein, whereas ectopic expression of HMGA2 is found to induce growth arrest in primary cells. The precise mechanisms underlying this phenomenon remain to be unravelled. In the present study, we determined that HMGA2 was able to induce apoptosis in WI38 primary human cells. We show that WI38 cells expressing high level of HMGA2 were arrested at G2/M phase and exhibited apoptotic nuclear phenotypes. Meanwhile, the cleaved caspase 3 (cysteine aspartic acid-specific protease 3) was detected 8 days after HMGA2 overexpression. Flow cytometric analysis confirmed that the ratio of cells undergoing apoptosis increased dramatically. Concurrently, other major apoptotic markers were also detected, including the up-regulation of p53, Bax and cleaved caspase 9, down-regulation of Bcl-2; as well as release of cytochrome c from the mitochondria. We further demonstrate that the shRNA (small-hairpin RNA)-mediated Apaf1 (apoptotic protease activating factor 1) silencing partially rescued the HMGA2-induced apoptosis, which was accompanied by the decrease of cleaved caspase-3 level and a decline of cell death ratio. Our results also reveal that γH2A was accumulated in nuclei during the HMGA2-induced apoptosis along with the up-regulation of cleaved caspase 2, suggesting that the HMGA2-induced apoptosis was dependent on the pathway of DNA damage. Overall, the present study unravelled a novel function of HMGA2 in induction of apoptosis in human primary cell lines, and provided clues for clarification of the mechanistic action of HMGA2 in addition to its function as an oncoprotein.

Cellular senescence is an irreversible form of cell cycle arrest that provides a barrier to neoplastic transformation. The integrity of the Rb (Retinoblastoma) pathway is necessary for the formation of the senescence-associated heterochromatin foci (SAHF) that offers a molecular basis for the stability of the senescent state. Surprisingly, although high mobility group A2 protein (HMGA2) can promote tumorigenesis and inhibit Rb function in tumor cells, high-level expression of HMGA2 is sufficient to induce SAHF formation in primary cells. It therefore becomes significant to determine whether Rb protein is necessary in HMGA2-induced SAHF formation. In this study, we established the cellular senescence and SAHF assembly WI38 cell model by ectopic expression of HMGA2, in which typical senescent markers were seen, including notable upregulation of p53, p21 and p16, and elevated SA-β-galactosidase staining together with downregulation of E2F target genes. We then showed that the Rb pathway inhibitor E7 protein was able to partly abolish the ability of SAHF formation after HMGA2 expression in WI38 cells, indicating that Rb is a crucial factor for HMGA2-induced SAHF formation. However, Rb depletion did not completely rescue the cell growth arrest induced by HMGA2, suggesting that Rb is not an exclusive pathway for HMGA2-induced senescence in WI38 cells.