Theranostic nanoparticles ZIF-8@ICG for pH/NIR-responsive drug-release and NIR-guided chemo-phototherapy against non-small-cell lung cancer.

This study leverages nanotechnology by encapsulating indocyanine green (ICG) and paclitaxel (Tax) using zeolitic imidazolate frameworks-8 (ZIF-8) as a scaffold. This study aims to investigate the chemo-photothermal therapeutic potential of ZIF-8@ICG@Tax nanoparticles (NPs) in the treatment of non-small cell lung cancer (NSCLC). An "all-in-one" theranostic ZIF-8@ICG@Tax NPs was conducted by self-assembly based on electrostatic interaction. First, the photothermal effect, stability, pH responsiveness, drug release, and blood compatibility of ZIF-8@ICG@Tax were evaluated through in vitro testing. Furthermore, the hepatic and renal toxicity of ZIF-8@ICG@Tax were assessed through in vivo testing. Additionally, the anticancer effects of these nanoparticles were investigated both in vitro and in vivo. Uniform and stable chemo-photothermal ZIF-8@ICG@Tax NPs had been successfully synthesized and had outstanding drug releasing capacities. Moreover, ZIF-8@ICG@Tax NPs showed remarkable responsiveness dependent both on pH in the tumor microenvironment and NIR irradiation, allowing for targeted drug delivery and controlled drug release. NIR irradiation can enhance the tumor cell response to ZIF-8@ICG@Tax uptake, thereby promoting the anti-tumor growth in vitro and in vivo. ZIF-8@ICG@Tax and NIR irradiation have demonstrated remarkable synergistic anti-tumor growth properties compared to their individual components. This novel theranostic chemo-photothermal NPs hold great potential as a viable treatment option for NSCLC.

C1632 suppresses the migration and proliferation of non-small-cell lung cancer cells involving LIN28 and FGFR1 pathway.

Chemoresistance and migration represent major obstacles in the therapy of non-small-cell lung cancer (NSCLC), which accounts for approximately 85% of lung cancer patients in clinic. In the present study, we report that the compound C1632 is preferentially distributed in the lung after oral administration in vivo with high bioavailability and limited inhibitory effects on CYP450 isoenzymes. We found that C1632 could simultaneously inhibit the expression of LIN28 and block FGFR1 signalling transduction in NSCLC A549 and A549R cells, resulting in significant decreases in the phosphorylation of focal adhesion kinase and the expression of matrix metalloproteinase-9. Consequently, C1632 effectively inhibited the migration and invasion of A549 and A549R cells. Meanwhile, C1632 significantly suppressed the cell viability and the colony formation of A549 and A549R cells by inhibiting DNA replication and inducing G0/G1 cell cycle arrest. Interestingly, compared with A549 cells, C1632 possesses the same or even better anti-migration and anti-proliferation effects on A549R cells, regardless of drug resistance. In addition, C1632 also displayed the capacity to inhibit the growth of A549R xenograft tumours in mice. Altogether, these findings reveal the potential of C1632 as a promising anti-NSCLC agent, especially for chemotherapy-resistant NSCLC treatment.

Identification of RET fusions in a Chinese multicancer retrospective analysis by next-generation sequencing.

Fusion of RET with different partner genes has been detected in papillary thyroid, lung, colorectal, pancreatic, and breast cancer. Approval of selpercatinib for treatment of lung and thyroid cancer with RET gene mutations or fusions calls for studies to explore RET fusion partners and their eligibility for RET-based targeted therapy. In this study, RET fusion patterns in a large group of Chinese cancer patients covering several cancer types were identified using next-generation sequencing. A total of 44 fusion patterns were identified in the study cohort with KIF5B, CCDC6, and ERC1 being the most common RET fusion partners. Notably, 17 novel fusions were first reported in this study. Prevalence of functional RET fusions was 1.05% in lung cancer, 6.03% in thyroid cancer, 0.39% in colorectal cancer, and less than 0.1% in gastric cancer and hepatocellular carcinoma. Analysis showed a preference for fusion partners in different tumor types, with KIF5B being the common type in lung cancer, CCDC6 in thyroid cancer, and NCOA4 in colorectal cancer. Co-occurrence of EGFR mutations and RET fusions with rare partner genes (rather than KIF5B) in lung cancer patients was correlated with epidermal growth factor receptor-tyrosine kinase inhibitor resistance and could predict response to targeted therapies. Findings from this study provide a guide to clinicians in determining tumors with specific fusion patterns as candidates for RET targeted therapies.

Down-regulation of MTHFD2 inhibits NSCLC progression by suppressing cycle-related genes.

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a bifunctional enzyme located in the mitochondria. It has been reported to be overexpressed in several malignancies. However, the relationship between the expression of MTHFD2 and non-small cell lung cancer (NSCLC) remains largely unknown. In this study, we found that MTHFD2 was significantly overexpressed in NSCLC tissues and cell lines. Knockdown of MTHFD2 resulted in reduced cell growth and tumorigenicity in vitro and in vivo. Besides, the mRNA and protein expression level of cell cycle genes, such as CCNA2, MCM7 and SKP2, was decreased in MTHFD2 knockdown H1299 cells. Our results indicate that the inhibitory effect of MTHFD2 knockdown on NSCLC may be mediated via suppressing cell cycle-related genes. These findings delineate the role of MTHFD2 in the development of NSCLC and may have potential applications in the treatment of NSCLC.

The value of F-18 fluorodeoxyglucose positron emission tomography/computed tomography in asymptomatic examinees with unexplained elevated blood carcinoembryonic antigen levels.

PURPOSE: Cancer is still a clinical challenge, with many efforts invested in order to achieve timely detection. Unexplained elevated blood carcinoembryonic antigen levels are occasionally observed in an asymptomatic population and considered as a risk factor of cancers. The purpose of this study was to determine the validity of 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography (F-18 FDG-PET/CT) for detecting cancer in an asymptomatic population with an unexplained elevation in blood carcinoembryonic antigen (CEA) levels. METHODS: This retrospective study included a total of 1920 asymptomatic examinees conducted from August 2011 through September 2013. The participants underwent CEA assay and conventional medical imaging (CEA-conventional), or CEA assay and F-18 FDG-PET/CT (CEA-PET/CT). The validity of conventional medical imaging and CEA-PET/CT scanning for detecting cancer and early-stage cancer in an asymptomatic population with an unexplained elevation in blood CEA levels were evaluated. RESULTS: Sensitivity, specificity, cancer detection rate, missed cancer detection rate, early-stage cancer detection rate, and early-stage cancer ratio using the CEA-PET/CT scanning were 96.6 %, 100 %, 10.4 %, 0.4 %, 3.7 %, and 34.5 %, respectively. In contrast, the corresponding values obtained using the conventional medical imaging were 50.6 % (P < 0.0001), 100 % (P > 0.9999), 50.6 % (P < 0.0001), 99.9 % (P = 0.055), 2.6 % (P < 0.0001), 2.5 % (P = 0.04), 0.7 % (P = 0.0004), and 14.5 % (P = 0.002), respectively. CONCLUSION: The F-18 FDG-PET/CT scanning significantly improved the validity of the cancer detection program in the asymptomatic population with an unexplained elevation in CEA levels.

MicroRNA-451 sensitizes lung cancer cells to cisplatin through regulation of Mcl-1.

As one of the most widely used chemotherapy drugs for lung cancer, chemoresistance of cisplatin (DPP) is one of the major hindrances in treatment of this malignancy. The microRNAs (miRNAs) have been identified to mediate chemotherapy drug resistance. MiR-451 as a tumor suppressor has been evaluated its potential effect on the sensitivity of cancer cells to DDP. However, the role of miR-451 in regulatory mechanism of chemosensitivity in lung cancer cells is still largely unknown. In this study, we first constructed a cisplatin-resistant A549 cell line (A549/DPP) accompanied with a decreased expression of miR-451 and an increased expression of Mcl-1in the drug resistant cells compared with the parental cells. Exogenous expression of miR-451 level in A549/DPP was found to sensitize their reaction to the treatment of cisplatin, which coincides with reduced expression of Mcl-1. Interestingly, Mcl-1 knockdown in A549/DPP cells increased the chemosensitivity to DPP, suggesting the dependence of Mcl-1 regulation in miR-451 activity. Moreover, miR-451 can restore cisplatin treatment response in cisplatin-resistant xenografts in vivo, while Mcl-1 protein levels were decreased. Thus, these findings provided that in lung cancer cells, tumor suppressor miR-451 enhanced DPP sensitivity via regulation of Mcl-1 expression, which could be served as a novel therapeutic target for the treatment of chemotherapy resistant in lung cancer.

K-Ras promotes the non-small lung cancer cells survival by cooperating with sirtuin 1 and p27 under ROS stimulation.

Cigarette smoking might lead to lung cancer. However, the related signaling pathways at molecular level remained unknown until now. In this study, we studied the signaling processes associated between tobacco exposure and lung cancer. First, we detected and validated pathway-specific gene expression at bronchial epithelium. These proteins reflected the activation of signaling pathways relevant to tobacco exposure, including ATM, BCL2, GPX1, K-Ras, IKBKB, and SIRT1. Tobacco smoking was simulated via reactive oxygen species (ROS) pathway. ROS not only arrested cell cycle at G1/S stage but also increased expressions of Sirt1 and p27. Further studies showed that the expression of p27 was dependent on ERK1/2 activation, and p27 itself could halt cell cycle by inhibiting the activation of CDKs. Moreover, activation of K-Ras, the key regulator of Ras/ERK pathway, was tightly regulated by enzyme activity of Sirt1. Deacetylation of K-Ras by Sirt1 increased the transformation of Ras-GTP to Ras-GDP, promoting the activation of downstream of ERK1/2. In reverse, Ras/ERK pathway could also regulate Sirt1 transcription. In conclusion, inhibition of Sirt1 may be an effective strategy for the prevention of tumor progression in high-risk patients or as a therapeutic strategy in established tumors.

Characterization of solitary pulmonary nodules with 18F-FDG PET/CT relative activity distribution analysis.

OBJECTIVES: To compare the capability of relative activity distribution (RAD), a new index of fluorodeoxyglucose F18 ((18)F-FDG) uptake, with those of the typical markers for differentiating benign and malignant solitary pulmonary nodules (SPNs) by integrated positron emission tomography (PET)/computed tomography (CT). METHODS: RAD, maximal standardised uptake value (SUV(max)), partial volume corrected SUV(max) (corrSUV(max)), and retention index (RI) were calculated prospectively for 115 malignant and 60 benign SPNs. Area under receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy were compared (P < 0.05). RESULTS: Malignant lesions (0.98 ± 0.03) had significantly lower RAD than benign lesions (1.01 ± 0.02). AUC (0.935) was significantly larger and specificity (96.67%) was significantly higher for RAD than for SUV(max) (P ≤ 0.0001), corrSUV(max) (P < 0.0001), RI (P < 0.0001), and visual assessment (P = 0.01 and 0.002, respectively). Further, RAD had significantly higher sensitivity (92.17%) than SUV(max) (P = 0.0007) and higher accuracy (93.71%) than SUV(max) (P < 0.0001), corrSUV(max) (P < 0.0001), and RI (P = 0.002). CONCLUSIONS: RAD seems to be more specific and accurate than the typical markers for differentiating malignant and benign SPNs by (18)F-FDG PET/CT. KEY POINTS: • Relative activity distribution index is assessable by (18)F-FDG PET/CT • The index effectively characterises solitary pulmonary nodules • RAD is more specific and accurate than the typical markers in (18)F-FDG PET/CT • RAD provides additional options for small solitary pulmonary nodules.

Multi-omics deep learning for radiation pneumonitis prediction in lung cancer patients underwent volumetric modulated arc therapy.

BACKGROUND AND OBJECTIVE: To evaluate the feasibility and accuracy of radiomics, dosiomics, and deep learning (DL) in predicting Radiation Pneumonitis (RP) in lung cancer patients underwent volumetric modulated arc therapy (VMAT) to improve radiotherapy safety and management. METHODS: Total of 318 and 31 lung cancer patients underwent VMAT from First Affiliated Hospital of Wenzhou Medical University (WMU) and Quzhou Affiliated Hospital of WMU were enrolled for training and external validation, respectively. Models based on radiomics (R), dosiomics (D), and combined radiomics and dosiomics features (R+D) were constructed and validated using three machine learning (ML) methods. DL models trained with CT (DLR), dose distribution (DLD), and combined CT and dose distribution (DL(R+D)) images were constructed. DL features were then extracted from the fully connected layers of the best-performing DL model to combine with features of the ML model with the best performance to construct models of R+DLR, D+DLD, R+D+DL(R+D)) for RP prediction. RESULTS: The R+D model achieved a best area under curve (AUC) of 0.84, 0.73, and 0.73 in the internal validation cohorts with Support Vector Machine (SVM), XGBoost, and Logistic Regression (LR), respectively. The DL(R+D) model achieved a best AUC of 0.89 and 0.86 using ResNet-34 in training and internal validation cohorts, respectively. The R+D+DL(R+D) model achieved a best performance in the external validation cohorts with an AUC, accuracy, sensitivity, and specificity of 0.81(0.62-0.99), 0.81, 0.84, and 0.67, respectively. CONCLUSIONS: The integration of radiomics, dosiomics, and DL features is feasible and accurate for the RP prediction to improve the management of lung cancer patients underwent VMAT.

Acetyl-cinobufagin suppresses triple-negative breast cancer progression by inhibiting the STAT3 pathway.

BACKGROUND: The incidence of breast cancer (BC) worldwide has increased substantially in recent years. Epithelial-mesenchymal transition (EMT) refers to a crucial event impacting tumor heterogeneity. Although cinobufagin acts as an effective anticancer agent, the clinical use of cinobufagin is limited due to its strong toxicity. Acetyl-cinobufagin, a pre-drug of cinobufagin, was developed and prepared with greater efficacy and lower toxicity. METHODS: A heterograft mouse model using triple negative breast cancer (TNBC) cell lines, was used to evaluate the potency of acetyl-cinobufagin. Signal transducer and stimulator of transcription 3 (STAT3)/EMT involvement was investigated by gene knockout experiments using siRNA and Western blot analysis. RESULTS: Acetyl-cinobufagin inhibited proliferation, migration, and cell cycle S/G2 transition and promoted apoptosis in TNBC cells in vitro. In general, IL6 triggered the phosphorylation of the transcription factor STAT3 thereby activating the STAT3 pathway and inducing EMT. Mechanistically, acetyl-cinobufagin suppressed the phosphorylation of the transcription factor STAT3 and blocked the interleukin (IL6)-triggered translocation of STAT3 to the cell nucleus. In addition, acetyl-cinobufagin suppressed EMT in TNBC by inhibiting the STAT3 pathway. Experiments in an animal model of breast cancer clearly showed that acetyl-cinobufagin was able to reduce tumor growth. CONCLUSIONS: The findings of this study support the potential clinical use of acetyl-cinobufagin as a STAT3 inhibitor in TNBC adjuvant therapy.

The Cancers-Specific Survival of Metastatic Pulmonary Carcinoids and Sites of Distant Metastasis: A Population-Based Study.

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths and pulmonary carcinoids (PCs) account for almost 2% of all pulmonary malignancies. However, few published articles have reported prognosis and related factors of pulmonary carcinoid patients. MATERIAL AND METHOD: The Surveillance, Epidemiology, and End Results (SEER) database was used to collect data of patients diagnosed with metastatic PCs from 2010 to 2016. The prognosis and survival of these patients were compared by employing Cox proportional hazards and the Kaplan-Meier survival analysis. RESULTS: A total of 1763 patients were analyzed. The liver (668, 25.6%) was shown to be the most common metastatic site in the isolated organ metastasis cohort, followed by the lung (636, 24.4%), bone (562, 21.6%), and brain (460, 17.6%). Among the patients, the tumor metastasized to a single distant site included the liver, bone, lung, and brain. Cancer-specific survival (CSS) in metastatic PCs is determined by the site of metastasis and the total number of such sites. Pulmonary carcinoid patients with isolated liver metastasis manifested more favorable survival rates in comparison to patients having isolated metastasis in the lung, brain, or bone. The median CSS was 45, 7, 6, 5 months (P = 0.011). The number of distant metastatic sites and the location of distant metastasis were found to be independent risk factors for CSS. For patients with distant isolated metastasis, liver metastasis (P < 0.0001) had better CSS in comparison to those with bone metastasis. When compared to patients whose carcinoids had metastasized to the bones, patients with a brain (P = 0.273) or lung (P = 0.483) metastasis had the same CSS. CONCLUSION: Cancer-specific survival in metastatic PCs depends on the site of metastasis and the total number of such locations. PC patients with isolated liver metastasis manifested more favorable survival in comparison to patients with isolated metastasis in the lung, brain, or bone.

Case Report: Next-Generation Sequencing Reveals Tumor Origin in a Female Patient With Brain Metastases.

BACKGROUND: Brain metastasis mainly originates from lung cancer. Napsin A and TTF-1 factors have frequently been detected in lung adenocarcinoma cases. Brain metastasis tumors with napsin A and TTF-1 positive are easily classified as lung adenocarcinoma origin. However, some thyroid cancers also exhibit these clinical features. Besides, lung is the most common metastasis of undifferential thyroid cancer. Therefore, it requires development of novel diagnostic tools to aid in distinguishing between pulmonary and thyroid origin. PATIENT FINDINGS: We reported a case that was initially diagnosed as brain metastatic lung cancer based on immunohistochemistry results. Analysis of next-generation sequencing (NGS) data from the brain lesion revealed that the cancer may have originated from the thyroid. We detected combo mutations in TERT promoter mutation, RET fusion and TP53, which are common in undifferential thyroid cancer (UTC), but rare for lung cancer. These results, coupled with identification of PAX8, indicated that this patient had UTC. Additionally, her three sons, despite being asymptomatic, were all diagnosed with papillary thyroid carcinoma. SUMMARY: The patient received anlotinib treatment and showed good clinical outcomes. One month after anlotinib treatment, the pulmonary nodules were found to be controlled, and the thyroid tumor drastically reduced, and tracheal compression relieved. She continued anlotinib treatment for the following two months, but died one month later because the treatment stopped owing to financial reasons. All her sons underwent total thyroidectomy with lymph node dissection. CONCLUSIONS: Although NGS has been reported to assist in diagnosis of the origin of some tumors, this is the first evidence of NGS for the determination of the origin of thyroid tumors. To our knowledge, this is the first time that a combination of multiple mutations has been used to help determine the origin of a tumor, compared with the previous single mutant gene. Moreover, this is the first evidence on the use of anlotinib for treatment of UTC with distant metastasis. Besides, all three sons of the patient had thyroid carcinoma in subsequent examinations, indicating high-risk for familial non-medullary thyroid cancer in UTC patients and necessity for performing thyroid ultrasound testing in other family members.

Mechanism of epithelial­mesenchymal transition inhibited by miR­203 in non­small cell lung cancer.

The aim of the present study was to investigate whether miR­203 can inhibit transforming growth factor­ß (TGF­ß)­induced epithelial­mesenchymal transition (EMT), and the migration and invasion ability of non­small cell lung cancer (NSCLC) cells by targeting SMAD3. In the present study, the expression levels of miR­203, SMAD3 mRNA and protein in NSCLC tissues were examined, as well as their corresponding paracancerous samples. The miR­203 mimics and miR­203 inhibitor were transfected into the H226 cell line. RT­qPCR was used to assess the expression levels of E­cadherin, Snail, N­cadherin and vimentin mRNA, and western blotting was performed to detect the expression levels of p­SMAD2, SMAD2, p­SMAD3, SMAD3 and SMAD4. The cell migration and invasion abilities were detected by Transwell assays. The target site of SMAD3 was predicted by the combined action between miR­203 and dual luciferase. The results revealed that the RNA levels of miR­203, compared with paracancerous tissues, were decreased in NSCLC tissues, while SMAD3 mRNA and protein levels were upregulated, and miR­203 inhibited SMAD3 expression. Induction of TGF­ß led to decreased E­cadherin mRNA levels, upregulation of Snail, N­cadherin and vimentin mRNA levels (P<0.05), and significant increase in cell migration and invasion, whereas transfection of miR­203 mimics reversed the aforementioned results (P<0.05). Conversely, miR­203 inhibitor could further aggravate the aforementioned results (P<0.05). Western blot results revealed that transfection of miR­203 mimics significantly reduced the protein expression of SMAD3 and p­SMAD3 (P<0.05). Furthermore, the results of the Dual­Luciferase assay revealed that miR­203 inhibited SMAD3 expression by interacting with specific regions of its 3'­UTR. Overall, a novel mechanism is revealed, in which, miR­203 can inhibit SMAD3 by interacting with specific regions of the 3'­UTR of SMAD3, thereby restraining TGF­ß­induced EMT progression and migration and invasion of NSCLC cells.

Clinical features and prognosis of primary tracheal small cell carcinoma: a population-based analysis.

BACKGROUND: Primary tracheal small cell carcinoma (SCC) is an uncommon malignancy; therefore, its clinical features and prognosis are still unclear. METHODS: We used the population-based Surveillance, Epidemiology, and End Results (SEER) database to elucidate the clinical features and prognosis of primary tracheal SCC. The clinical features were assessed by using the chi-square test. Overall survival (OS) was computed using the Kaplan-Meier method, and a Cox proportional hazards analysis was performed to evaluate the prognostic factors. RESULTS: From 1973 to 2015, 1,392 primary tracheal tumor cases were reported in the SEER database, 75 (5.4%) of which were SCC. Age, sex, race, extent of disease, lymph node involvement, surgery and radiation treatment were similar between patients with SCC and those with squamous cell carcinoma (SQC), but patients with SCC were more likely to receive chemotherapy (65.8% vs. 28.2%, respectively; P<0.001). The 1-, 3- and 5-year OS rates of patients with SCC were 37.8%, 12.4% and 7.1%, respectively, and the median survival duration was 10.0 months, which was much worse than that observed for patients with other histopathological types of tracheal cancer. Among patients aged 60-100 years and those with regional lymph node involvement, the OS for patients with SQC was superior to that for patients with SCC (P=0.034 and P=0.016, respectively). According to the multivariate analysis, age and lymph node involvement are independent prognostic factors of SCC. CONCLUSION: Primary tracheal SCC is a rare carcinoma with a poor prognosis. Age and lymph node involvement are independent prognostic factors of SCC.

Survival nomogram for patients with metastatic siewert type II adenocarcinoma of the esophagogastric junction: a population-based study.

BACKGROUND: The aim of this study was to construct a nomogram to predict the survival of patients with metastatic Siewert Type II adenocarcinomas of the esophagogastric junction (AEG). METHODS: Patients were identified using the Surveillance, Epidemiology, and End Results (SEER) database. Cox regression analysis was performed to assess the prognostic factors. A nomogram comprising independent prognostic factors was established and evaluated using C-indexes, calibration curves, and decision curve analyses. RESULTS: In total 1616 eligible patients were enrolled. Race, age, bone metastasis, liver metastasis, lung metastasis, other metastasis sites, and distant lymph nodes metastasis were independent prognostic factors and were integrated to construct the nomogram. The nomogram had a C-index of 0.590 (95% CI: 0.569-0.611) in the training cohort and 0.569 (95% CI: 0.532-0.606) in the validation cohort. The calibration plots for the probabilities of 6-month and 1-year overall survival demonstrated there was an optimum between nomogram prediction and actual observation. CONCLUSION: We developed and validated a nomogram to predict individual prognosis for patients with metastatic Siewert Type II AEG, and the risk stratification system based on the nomogram could effectively stratify the patients into two risk subgroups, which can help clinicians accurately predict mortality risk and recommend personalized treatment modalities.

Sites of distant metastases and the cancer-specific survival of metastatic Siewert type II esophagogastric junction adenocarcinoma: a population-based study.

BACKGROUND: The effect of distant metastasis on prognosis in patients with Siewert type II adenocarcinoma of the esophagogastric junction (AEG) remains elusive. METHODS: Patients diagnosed as metastatic Siewert type II AEG were identified using the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier survival analysis and a Cox proportional hazards analysis were performed to assess the effect of distant metastases sites. RESULTS: We analyzed 1616 eligible patients. Liver was the most frequent metastatic site. For patients with isolated distant metastasis, the median survival time was 8, 7, 8, 10, and 11 months for patients with liver, bone, brain, lung, and distant lymph nodal metastasis, respectively (p = 0.011). The number of metastatic sites and the site of distant metastasis were independent prognostic factors for cancer-specific survival (CSS). In patients with isolated distant metastasis, using bone metastasis as reference, lung (p = 0.011) or distant lymph node metastasis (p = 0.030) was associated with better CSS, while patients with liver (p = 0.051) or brain (p = 0.488) metastasis had similar CSS compared to patients with bone metastasis. CONCLUSION: CSS in metastatic Siewert type II AEG is dependent on the metastatic site and the number of metastatic sites.

Gephyrin suppresses lung squamous cell carcinoma development by reducing mTOR pathway activation.

Background: The mTOR pathway is altered in a multitude of cancers, including lung cancer; however, abnormal activation in this pathway is less common in lung adenocarcinoma (LUAD) than in lung squamous cell carcinoma (LUSC). Gephyrin is a highly conserved and widely expressed ancient protein in vertebrate tissues. Its role and molecular mechanism in lung cancer development are largely unknown. Method: We analyzed the expression profile of gephyrin and overall survival rates in LUAD and LUSC. The LUSC cells (H520 and SK-MES-1) were transfected with pLV-gephyrin to establish gephyrin stable overexpression cell lines. Real-time quantitative PCR and Western blot were performed to detect the mRNA and protein levels. The cell growth and cell cycle were detected by the MTT assay and flow cytometry. Finally, a xenograft tumor model was established to determine cell tumorigenesis in vivo. Results: Our results show that gephyrin was reduced in LUAD and LUSC, and its low expression in LUSC patients indicated poor prognosis. Gephyrin overexpression suppressed LUSC cell proliferation, arrested cell cycle progression, and decreased the expression of cell-cycle related proteins such as cyclin D1, cyclin-dependent kinase-2 (CDK2), and proliferation-related protein proliferating cell nuclear antigen (PCNA). Conversely, knockdown of gephyrin promoted LUSC cell growth. Moreover, gephyrin reduced mTOR pathway activation to inhibit cyclin D1 and CDK2 translation. Mechanistically, gephyrin suppressed mTOR pathway activation by promoting mTOR degradation. Furthermore, gephyrin overexpression suppressed LUSC tumorigenesis. Conclusion: Gephyrin suppressed LUSC development by reducing mTOR pathway activation, implicating gephyrin as a potential molecular target for LUSC management.

Tumor shrinkage rate as a potential marker for the prediction of long-term outcome in advanced non-small cell lung cancer treated with first-line tyrosine kinase inhibitors.

CONTEXT: Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) play an indispensable role in the treatment of non-small cell lung cancer (NSCLC), leading to a survival major breakthrough, but there remains no uniform standard for predicting the efficacy of TKI therapy. AIMS: We retrospectively reviewed the use of EGFR-TKIs for advanced NSCLC between January 2009 and December 2017 in a hospital, which 169 patients who treated with first-line TKIs were enrolled. SUBJECTS AND METHODS: Multiple clinical factors, including histology, age, and sex, were analyzed. We calculated the tumor shrinkage rate (TSR) by measuring the longest diameters of the main mass by computed tomography (CT) before TKI therapy and the first CT after TKI therapy. We evaluated overall survival (OS) and progression-free survival (PFS) after first-line TKI therapy, and we assessed factors predicting survival using the Kaplan-Meier method. RESULTS: Eligible patients were sorted into higher (n = 83) and lower (n = 86) TSR groups according to the mean TSR of 0.49%. The 83 patients with a higher TSR had longer PFS and OS than those in the 86 patients with a lower TSR (14.83 vs. 8.40 months, P < 0.001, and 31.03 vs. 20.10 months, P < 0.001, respectively). Multivariate analyses revealed that TSR was an independent predictor of PFS and OS (PFS hazard ratio [HR]: 0.506, P < 0.001, and OS HR: 0.291, P < 0.001). CONCLUSIONS: These cumulative data support that TSR may be an early predictor of the treatment efficacy in NSCLC with EGFR mutations treated with first-line TKIs.

LncRNA PRNCR1 interacts with HEY2 to abolish miR-448-mediated growth inhibition in non-small cell lung cancer.

It has been announced in accumulative studies that non-coding (nc)RNAs are responsible for a varieties of biological behaviors during the progression of tumors. As two subgroups of ncRNAs family, micro (mi)RNAs can interact with long non-coding (lnc)RNAs, thereby forming ceRNA network. In this study, miR-448 was expressed higher in NSCLC tissues (P < 0.01) and NSCLC cell lines (P < 0.01). Moreover, low expression of miR-448 predicted poor prognosis for patients with NSCLC (P < 0.001). Functional assays revealed the anti-oncogenic function of miR-448 in NSCLC by inhibiting cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT). Mechanically, miR-448 was found to be negatively regulated by lncRNA PRNCR1 (prostate cancer non-coding RNA 1). Moreover, HEY2 (Hairy and enhancer of split-related with YRPW motif protein 2) was demonstrated to be the target mRNA of miR-448 in NSCLC cells. All mechanism experiments revealed that lncRNA PRNCR1 exerted ceRNA function in NSCLC by regulating miR-448 and HEY2. To validate the function of PRNCR1-miR-488-HEY2 network in NSCLC progression, rescue assays were conducted. Taken all together, we confirmed that lncRNA PRNCR1 upregulates HEY2 to promote tumor progression in NSCLC by competitively binding miR-448.

PRMT7 contributes to the metastasis phenotype in human non-small-cell lung cancer cells possibly through the interaction with HSPA5 and EEF2.

BACKGROUND: Non-small-cell lung cancer (NSCLC) constitutes the leading cause of cancer death in humans. Previous studies revealed the essential role of the protein arginine methyltransferase 7 (PRMT7) in promoting metastasis in breast cancer. However, its function and potential mechanism in NSCLC remain unclear. MATERIALS AND METHODS: The gene expression of PRMT7 between lung cancer tissues and normal tissues was studied with online database (http://medicalgenome.kribb.re.kr/GENT/). NSCLC cell lines with specific gene overexpression were constructed with lentivirus transduction. Matrigel invasion and colony formation assays were performed to evaluate the invasion and colony formation abilities. Co-immunoprecipitation coupled with mass spectrometry analysis was performed to explore the potential interaction proteins of PRMT7. Bioinformatic analysis was performed with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. RESULTS: Online analysis of gene expression patterns revealed the relatively high expression of PRMT7 in lung cancer tissues. PRMT7 overexpression was able to promote the invasion and colony formation of A549 and SPC-A1 cells. A total of 19 in-common proteins shared by both NSCLC cell lines were identified to be interacting with PRMT7 and found to participate in a wide variety of pathways and protein-protein interactions according to bioinformatic analysis. Among them, HSPA5 and EEF2 were further investigated for their essential roles in PRMT7-promoted NSCLC cell invasion. CONCLUSION: Our results suggested PRMT7 overexpression was able to promote metastasis in NSCLC possibly through the interaction with HSPA5 and EEF2, which provides the potential mechanism of oncogenesis in lung cancer.