The Mechanics of Tumor Cells Dictate Malignancy via Cytoskeleton-Mediated APC/Wnt/ß-Catenin Signaling.

Tumor cells progressively remodel cytoskeletal structures and reduce cellular stiffness during tumor progression, implicating the correlation between cell mechanics and malignancy. However, the roles of tumor cell cytoskeleton and the mechanics in tumor progression remain incompletely understood. We report that softening/stiffening tumor cells by targeting actomyosin promotes/suppresses self-renewal in vitro and tumorigenic potential in vivo. Weakening/strengthening actin cytoskeleton impairs/reinforces the interaction between adenomatous polyposis coli (APC) and ß-catenin, which facilitates ß-catenin nuclear/cytoplasmic localization. Nuclear ß-catenin binds to the promoter of Oct4, which enhances its transcription that is crucial in sustaining self-renewal and malignancy. These results demonstrate that the mechanics of tumor cells dictate self-renewal through cytoskeleton-APC-Wnt/ß-catenin-Oct4 signaling, which are correlated with tumor differentiation and patient survival. This study unveils an uncovered regulatory role of cell mechanics in self-renewal and malignancy, and identifies tumor cell mechanics as a hallmark not only for cancer diagnosis but also for mechanotargeting.

Gallincin ameliorates colitis-associated inflammation and barrier function in mice based on network pharmacology prediction.

OBJECTIVE: To explore potential mechanisms and effects of gallincin on a mouse model of colitis induced by dextran sulfate sodium (DSS). METHODS: Network pharmacology analysis was used to predict the molecular mechanism of action of gallincin for treatment of colitis. Gallincin was administered orally to mice with DSS-induced colitis. Expression of tumor necrosis factor α (TNF-α), D-lactate, and interleukin-1ß (IL-1ß) and myeloperoxidase activity were assessed with real-time quantitative PCR and an enzyme-linked immunoassay, respectively. Expression of occludin, zonula occludens 1 (ZO-1), and phosphorylated extracellular signal-regulated protein kinase1/2 (p-ERK1/2) was analyzed with immunohistochemical staining and/or western blot assays. RESULTS: Using a network pharmacology approach, 12 mapping targets between gallincin and colitis were obtained, including ERK/mitogen-activated protein kinase. Further investigations in an experimental colitis mouse model showed that gallincin significantly ameliorated experimental colitis, reduced D-lactate levels, and remarkably increased occludin and ZO-1 expression, possibly in part by decreasing IL-1ß, TNF-α, and p-ERK1/2 levels and inhibiting leukocyte penetration. CONCLUSIONS: Gallincin regulated colonic barrier function and reduced colitis-associated inflammation, suggesting it is a promising drug for the treatment of ulcerative colitis.

Detection of ALK Gene Rearrangement in Cell-free RNA from Lung Cancer Malignant Pleural Effusion.

The aim of this study was to evaluate the feasibility of measuring ALK gene rearrangement in cell-free RNA (cf-RNA) of the supernatant from malignant pleural effusion (MPE). Supernatant, cell blocks, and matched sera samples were collected. Cf-RNA was isolated from the supernatant and sera, and cellular RNA was isolated from cell blocks. The ALK gene rearrangement in the cf-RNA was tested by the real-time polymerase chain reaction. Results showed that the concentration of cf-RNA was higher in the supernatant than in matched sera. ALK status concordance rates were 100% between the supernatant and cell blocks, while they were 0% between sera and cell blocks in ALK gene rearrangement cases. This suggests that using cf-RNA in MPE supernatant, but not in sera, could offer a reliable and robust surrogate strategy for the detection of ALK gene rearrangement.

Identification of upstream miRNAs of SNAI2 and their influence on the metastasis of gastrointestinal stromal tumors.

BACKGROUND: SNAI2, a member of the snail zinc finger protein family, plays an important role in the metastasis of several types of carcinoma. OBJECTIVE: This study aims to investigate the upstream miRNAs of SNAI2 and their influence on the metastasis of gastrointestinal stromal tumors (GISTs). METHODS: The expression levels of SNAI2, CDH1, and CDH2 in GISTs were determined by immunohistochemistry, and the correlations with their clinicopathologic characteristics were analyzed. Subsequently, the miRNAs involved in regulating SNAI2 expression were predicted by bioinformatics technique, screened by miRNA microarray tests, and verified by real-time PCR, dual luciferase reporter assay, and invasion assay. The influence of SNAI2 and miRNAs on the invasive ability of the GIST cells and the related mechanism were detected. OUTCOMES: SNAI2 expression significantly increased and CDH1 expression markedly decreased in the cases of GISTs with distant metastasis. Silencing of the SNAI2 gene impaired the invasiveness of GIST cells in vitro. MiR-200b-3p, miR-30c-1-3P, and miR-363-3P were verified as the upstream metastasis-associated miRNAs of SNAI2 in GISTs by miRNA microarray, real-time PCR, dual luciferase reporter assay, and invasion assay. They bound to the 3'-UTR of SNAI2, downregulated SNAI2 expression, and inhibited the invasiveness of GIST cells. SNAI2 targetedly bound to the promoter of the CDH1 gene, downregulated the expression of CDH1, and contributed to the metastasis of GISTs. CONCLUSION: SNAI2 and CDH1 correlated with the metastasis of GISTs, and silencing of the SNAI2 gene impaired the invasiveness of GIST cells. MiR-200b-3p, miR-30c-1-3P, and miR-363-3P contribute to the metastasis of GISTs in vitro by mediating the SNAI2/CDH1 axis. SNAI2 may be a potential target for the treatment of GISTs in the future.

PARP6 acts as an oncogene and positively regulates Survivin in gastric cancer.

Poly (ADP-ribose) polymerases 6 (PARP6) is a novel member of the PARP family. Previous studies focused mostly on the role of PARP6 in colorectal cancer; however, the role of PARP6 in gastric cancer is currently unclear. In the present study, we found a high-level expression of PARP6 in gastric cancer cells and PARP6 promoted cell proliferation, migration and invasion. Moreover, we found a positive correlation exists between PARP6 and Survivin, which contributes to tumor ongoing survival. In sum, our data suggest that PARP6 may contribute to gastric cancer progression by activating the Survivin pathway.

Impact of age on EGFR mutations in never-smoking female lung adenocarcinoma patients with malignant pleural effusion.

Our aim was to evaluate EGFR mutations in never-smoking female lung adenocarcinoma patients with malignant pleural effusion and to reveal the relationship between age and EGFR mutations. Never-smoking female lung adenocarcinoma patients were retrospectively studied, including 301 biopsy samples and 80 cytological specimens. Our results showed a significant increase of EGFR mutation prevalence by increase of age in cytological specimens, but not in biopsy samples. Our data suggests that age at the time of diagnosis may be associated with presence of EGFR mutations in patients with malignant pleural effusion.

P1-HNF4α expression negatively correlates with HER2 levels and is associated with good prognosis in gastric adenocarcinoma.

HNF4α, a member of the steroid/thyroid nuclear receptor super family, is a transcriptional factor expressed in various tissues and cells. In this study, we aimed to investigate the clinical significance of P1-HNF4α protein expression in gastric adenocarcinoma. We examined P1-HNF4α and HER2 protein levels in the tissue of 245 gastric adenocarcinoma samples by immunohistochemistry, and analyzed the association between P1-HNF4α levels, and clinicopathologic factors or prognosis. In gastric adenocarcinoma, positive staining of P1-HNF4α was shown in 150 (61.2%) of 245 cases, while positive expression of HER2 was shown in 36 (14.7%) of 245 cases as detected by immunohistochemistry. The expression of P1-HNF4α was negatively correlated with that of HER2. Furthermore, P1-HNF4α and HER2 highly expressed in intestinal-type adenocarcinoma according to the Lauren classification, tubular adenocarcinoma according to WHO classification, and well-to-moderately differentiated tumors. In gastric adenocarcinoma, P1-HNF4α was significantly associated with histological type, Lauren grade, degree of tumor differentiation, vascular invasion, lymph node metastases, and pTNM stage. Moreover, survival analysis showed that P1-HNF4α expression was an independent prognostic factor of good survival in gastric adenocarcinoma (P<0.05). Our results indicate that a negative correlation exists between P1-HNF4α and HER2 expression levels and P1-HNF4α is significantly correlated with tumor progression and a good prognosis in gastric adenocarcinoma.

Integration of multiple disciplines on primary breast bidirectional synovial sarcoma / 中国肿瘤临床

Objective:To explore the diagnosis and treatment process of integrated multiple disciplines on primary bidirectional synovi-al sarcoma in breasts. Methods:A patient with breast sarcoma was diagnosed and treated with body satisfaction scale (BSS) on May 2017 in the Department of Breast Surgery of Guizhou Provincial People's Hospital. Procedures were fully discussed. The patient was prepared for the surgery and was successfully treated by palliative resection (in the right breast tumor) and partial pectoralis major muscle resection and reconstruction (in the chest wall flap). Results:Patient's condition and quality of life significantly improved. Ex-tended treatment was provided for continuous survival. Conclusion:Prognosis of primary bidirectional synovial sarcoma of the breasts can be improved by early diagnosis and treatment. Patient's willingness of medical consultation could affect the ontcome.

Primary monophasic synovial sarcoma of the liver in a 13-year-old boy.

Synovial sarcoma originating in the liver is extremely rare, and thus far only 3 cases have been reported in the English literature. Herein, we report a primary hepatic synovial sarcoma in a 13-year-old Chinese boy. This patient present with a 10-day right upper quadrant pain, and a heterogeneous mass was documented in the right hepatic lobe by computed tomography. Subsequently, the patient underwent right hepatectomy. Histologically, the tumor exhibited classic features of monophasic synovial sarcoma. The diagnosis was confirmed by the presence of SS18 gene rearrangement and identification of SS18-SSX1 fusion transcript. Unfortunately, a relapsing mass was detected 11 months after the surgery. To the best of our knowledge, the current case is the 1st published example in the pediatric population.