Chronic Stress Dampens Lactobacillus Johnsonii-Mediated Tumor Suppression to Enhance Colorectal Cancer Progression.

Colorectal cancer development and outcome are impacted by modifiable risk factors, including psychologic stress. The gut microbiota has also been shown to be linked to psychologic factors. Here, we found a marked deteriorative effect of chronic stress in multiple colorectal cancer models, including chemically induced (AOM/DSS), genetically engineered (APCmin/+), and xenograft tumor mouse models. RNA sequencing data from colon tissues revealed that expression of stemness-related genes was upregulated in the stressed colorectal cancer group by activated ß-catenin signaling, which was further confirmed by results from ex vivo organoid analyses as well as in vitro and in vivo cell tumorigenicity assays. 16S rRNA sequencing of the gut microbiota showed that chronic stress disrupted gut microbes, and antibiotic treatment and fecal microbiota transplantation abolished the stimulatory effects of chronic stress on colorectal cancer progression. Stressed colorectal cancer mice displayed a significant decrease in Lactobacillus johnsonii (L. johnsonii) abundance, which was inversely correlated with tumor load. Moreover, protocatechuic acid (PCA) was identified as a beneficial metabolite produced by L. johnsonii based on metabolome sequencing and LC/MS-MS analysis. Replenishment of L. johnsonii or PCA blocked chronic stress-induced colorectal cancer progression by decreasing ß-catenin expression. Furthermore, PCA activated the cGMP pathway, and the cGMP agonist sildenafil abolished the effects of chronic stress on colorectal cancer. Altogether, these data identify that stress impacts the gut microbiome to support colorectal cancer progression. SIGNIFICANCE: Chronic stress stimulates cancer stemness by reducing the intestinal abundance of L. johnsonii and its metabolite PCA to enhance ß-catenin signaling, forming a basis for potential strategies to circumvent stress-induced cancer aggressiveness. See related commentary by McCollum and Shah, p. 645.

Circ_0017639 facilitates proliferative, migratory, and invasive potential of non-small cell lung cancer (NSCLC) cells via PI3K/AKT signaling pathway.

Non-small cell lung cancer (NSCLC) has increased morbidity and mortality rate worldwide. The current NSCLS therapies are associated with poor outcomes and need further improvement. CircRNAs were shown to regulate NSCLC progression. However, little is known re garding the functions and mechanisms of circ_0017639 in NSCLC, which requires further extensive studies. The circ_0017639 expression in NSCLC tissues and cell lines was evaluated via qRT-RCR. Moreover, using ectopic plasmid incorporation and shRNA assays, we analyzed the circ_0017639-mediated cellular proliferative, migratory and invasive processes in NSCLC cell lines, using CCK-8, EdU, and transwell assays. Furthermore, the core proteins (p-PI3K, PI3K, p-AKT, and AKT) levels of the PI3K/AKT signaling cascade were investigated via immunoblotting. Finally, we tested the functional role of circ_0017639 by examining its regulation of xenograft tumor growths in nude mice in vivo. Circ_0017639 expression was remarkably high in the NSCLC tissues and cell lines. The transfection experiments showed that circ_0017639 overexpression was able to promote proliferative, migratory, and invasive properties of NSCLC cells, while sh-circ_0017639 showed opposing effects. We further showed that circ_0017639 knockdown suppressed the cellular development via PI3K/AKT cascade inactivation. Additionally, in-vivo experiment in nude mice demonstrated that sh-circ_0017639 could reduce the tumor growth of NSCLC. Circ_0017639 may promote the development of NSCLC by accelerating NSCLC metastasis through stimulating the PI3K/AKT cascade.

Comprehensive analysis of lncRNAs as biomarkers for diagnosis, prognosis, and treatment response in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common histological type of renal carcinoma and has a high recurrence rate and poor outcome. Accurate patient risk stratification based on genetic markers can help to identify the high-risk patient for early and further treatments and would promote patient survival. Long non-coding RNAs (lncRNAs) have attracted widespread attention as biomarkers for early diagnosis, treatment, and prognosis because of their high specificity and sensitivity. Here, we performed a systematic search in NCBI PubMed and found 44 lncRNAs as oncogenes, 18 lncRNAs as tumor suppressors, 199 lncRNAs as diagnostic biomarkers, 62 lncRNAs as prognostic biomarkers, and 3 lncRNAs as predictive biomarkers for ccRCC. We also comprehensively discuss the biological functions and molecular regulatory mechanisms of lncRNAs in ccRCC. Overall, the present study is a systemic analysis to assess the expression and clinical value of lncRNAs in ccRCC, and lncRNAs hold promise to be diagnostic, prognostic, and predictive biomarkers.

Gefitinib versus Docetaxel in Treated Non-small-cell Lung Cancer: A Meta-analysis.

The objective of this study was to perform a meta-analysis to evaluate the efficacy and toxicity of gefitinib and docetaxel in treated patients with non-small-cell lung cancer (NSCLC). METHODS: A literature search was performed using PubMed and CNKI databases for relevant keywords and the Medical Subject Headings. After further full-text screening, 10 clinical trials were included in the final meta-analysis. Specific odds ratios (OR) and confidence intervals were calculated. RESULTS: The outcomes of treatment efficacy included disease control rates, quality-of-life improvement rates, 3~4 grade adverse events. Comparing gefitinib to docetaxel for NSCLC patients, the pooled odds ratios (OR) of disease control rates was 1.09, (95% confidential index [CI] = 0.84-1.43), the pooled OR of quality-of-life improvement rates was 2.49, (95% CI = 1.77-3.49), the pooled OR of 3~4 grade adverse events was 0.49, (95% CI = 0.32-0.75). CONCLUSION: Gefitinib was found to significantly improve patients' quality-of-life and obviously decrease patients' adverse events of 3~4 grade.There is no difference of disease control rates between gefitinib and docetaxel.

[Comparison of Clinical Outcomes of VATS and SBRT in the Treatment of NSCLC].

BACKGROUND AND OBJECTIVE: More and more chest physicians chose video-assisted thoracoscopic surgery (VATS) to treat early stage non-small cell lung cancer (NSCLC). In recent years, there is still lack of a random trial comparing the clinical outcomes of VATS and stereotactic body radiotherapy (SBRT) in treating NSCLC. To provide a reference for the choice between VATS and SBRT, in the current meta-analysis, we compared the clinical outcomes of these two therapies in treating NSCLC. METHODS: Five major medical databases, CNKI, CPVIP (http://www.cqvip.com/), PubMed, Embase, and ISI web of science were systematically searched to identify all studies from January 2010 to February 2016 on VATS and SBRT therapies. Finally, original English or Chinese publications of stage I and II NSCLC with adequate patients and adequate SBRT doses were enrolled. A multivariate random effects model was used to perform a meta-analysis to compare overall survival and disease free survival between VATS and SBRT while adjusting for median age and operable patient numbers. RESULTS: Fourteen VATS studies (included 3,482 patients) and nineteen SBRT studies (included 3,997 patients) published in the same period were eligible. The median age and follow-up duration were 64 years and 43.4 months for VATS patients and 74 years and 29.5 months for SBRT patients, respectively. The mean unadjusted overall survival rates at 1, 2, 3, and 5 years with VATS were 93.5%, 84.9%, 77.0% and 76.3% compared to 89.0% 73.3% 59.0% and 36.7% with SBRT. The mean unadjusted disease free survival rates at 1, 2, 3, and 5 years with VATS were 93.6%, 88.6%, 85.6% and 75.6% compared to 79.3%, 72.1%, 64.9% and 58.9% with SBRT. While, after adjusted for proportion of operable patients and median age, the estimate overall survival rates at 1, 2, 3, and 5 years with VATS were 94%, 92%, 84% and 71% compared to 98%, 95%, 87% and 83% with SBRT. And the estimate disease free survival rates at 1, 2, 3, and 5 years with VATS were 97%, 94%, 85% and 75% compared to 88%, 81%, 74% and 63% with SBRT. CONCLUSION: Before adjustment, the SBRT group showed worse clinical outcomes (overall survival and disease free survival) than VATS group. When take consider of median age and operability, the patients with SBRT differ substantially from patients treated with VATS. After adjustment of median age and operability, there are no significant differences between these two therapy in treating NSCLC.

[Effect of dihydroartemisinin combined irradiation on the apoptosis of human lung cancer GLC-82 cells and its mechanism study].

OBJECTIVE: To study the effect of dihydroartemisinin (DHA) combined irradiation on the apoptosis of human lung cancer GLC-82 cells and to study its mechanism. METHODS: The growth inhibition rate of GLC-82 cells acted by different concentrations DHA was detected using MTT assay at 24, 48, and 72 h, respectively. Clone forming test was used. With multi-target single-hit model, the radiosensitization effect was assessed by calculating sensitizing enhancement ratio (SER).The effect of DHA combined irradiation on the apoptosis of GLC-82 cell cycle distribution and apoptosis were measured by flow cytometry. The protein expression of p53, p21, Bcl-2, and Bax were detected by Western blot. RESULTS: Different concentrations DHA (4, 8, 16, 32, 64, and 128 µg/mL) had cytotoxicity on GLC-82 cells. The IC50 for 24, 48, and 72 h was 38.25,20.58, and 10.36 µg/mL, respectively, in obvious dose- and time-dependent manner. The growth inhibition rate was more significantly increased than that of the blank control group (P < 0.01, P<0.05). DHA had sensitization enhancement effect on GLC-82 cells, with SER of 1.4. DHA combined irradiation could obviously change the structure of GLC-82 cells cell cycle and induce apoptosis (with the apoptosis rate of 21.5%), which was significantly different from that of the blank control group (P < 0.05). Western blot showed the expression of p53 and p21 protein could be increased by DHA combined irradiation, and the expression of Bcl-2 protein down-regulated (P <0.01, P <0. 05). CONCLUSIONS: DHA had stronger cytotoxicity and radiosensitization on GLC-82 cells. Its mechanisms might lie in making the arrest of GLC-82 cells' growth at G0/G1 phase, decreasing the ratio of cells at S phase, restoring the function of p53, decreasing the expression of Bcl-2 protein, and inducing apoptosis in GLC-82 cells.