The hepatic microenvironment promotes lung adenocarcinoma cell proliferation, metastasis, and epithelial-mesenchymal transition via METTL3-mediated N6-methyladenosine modification of YAP1.

The inflammatory microenvironment plays an important role in the onset and progression of lung adenocarcinoma (LUAD), and the liver is a suitable site of metastasis for LUAD cells. However, whether the inflammatory microenvironment of the liver is conducive to the proliferation, invasion, and metastasis of LUAD cells remains unclear. In this study, we confirmed that the hepatic inflammatory microenvironment stimulated by IL-6 promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition of LUAD cells, increased the m6A methylation of total RNA, and transcriptionally activated METTL3 expression. Additionally, METTL3 activated the YAP1/TEAD signaling pathway by increasing the m6A modification and expression of YAP1 mRNA. These results indicate that the hepatic inflammatory microenvironment plays a role in regulating the biological functions of LUAD cells. Further, our study identifies a molecular mechanism that may provide a new strategy for the early diagnosis, treatment, and prognosis of liver metastasis in LUAD patients.

Expression of PD-L1 in ovarian cancer and its synergistic antitumor effect with PARP inhibitor.

BACKGROUND: Ovarian cancer samples were studied to determine the expression of programmed death ligand-1 (PD-L1) and its relationship with prognosis, and to explore the effect and potential mechanism of a PARP inhibitor combined with PD-L1 monoclonal antibody for the treatment of ovarian cancer. MATERIALS AND METHODS: PD-L1 expression in paraffin-embedded tissues of ovarian cancer was detected by immunohistochemistry (IHC). Flow cytometry was used to detect PD-L1 expression in TILs. Furthermore, we investigated the mechanism of the upregulation of PD-L1 expression by PARP inhibitors in vitro and verified the combined effect in vivo. RESULTS: Our study demonstrated that PD-L1 expression in ovarian cancer tissues was associated with the FIGO stage (P = 0.026). OS was significantly lower in high PD-L1 expression group than in the low expression group (P = 0.0005, HR = 2.689), PD-L1 high expression (P = 0.023, HR = 2.275) and FIGO stage (P = 0.024, HR = 11.229) were independent risk factors affecting the survival and prognosis of ovarian cancer patients. Flow cytometry test suggested that PD-L1+ expression was negatively correlated with CD8+ T cell count in ovarian cancer cells (P = 0.054, r = -0.624). In vitro experiments revealed that PD-L1 expression of ovarian cancer cell lines was upregulated after intervention with PARP inhibitors through the Chk1 pathway. The results of in vivo experiments suggested that the growth volume and quality of tumors in the combination group were significantly lower than those in control group (P < 0.05). CONCLUSIONS: PARP inhibitors could induce upregulation of PD-L1 expression by promoting phosphorylation of chk1. Antagonistic PD-L1 could reverse the inhibitory effect of PARP inhibitors on CD8+T cells, and had synergistic antitumor effect with PARP inhibitors.

Decreased IFIT2 Expression Promotes Gastric Cancer Progression and Predicts Poor Prognosis of the Patients.

BACKGROUND/AIMS: The status of interferon (IFN) signaling pathway has been shown to be closely associated with the response of immune checkpoint blockade therapy against advanced human cancers. IFN-induced protein with tetratricopeptide repeats 2 (IFIT2), also known as IFN-stimulated gene 54 (ISG54), is one of the most highly responsive ISGs, which can inhibit the proliferation and migration of cancer cells, and regulate viral replication, resulting in anti-cancer and anti-viral effects. In the present study, we aimed to investigate the role of IFIT2 in human gastric cancer. METHODS: Immunohistochemistry assay was used to investigate the correlation between the IFIT2 expression in cancer tissues and clinical parameters of gastric cancer patients. Knockdown of IFIT2 was performed using RNAi to assess the role of IFIT2 in the regulation of biological behaviors in human gastric cancer cell lines. RESULTS: IFIT2 expression in gastric cancer tissues was significantly associated with tumor stage and postoperative prognoses of the patients. Moreover, decreased IFIT2 expression in human gastric cancer cell lines SGC-7901 and AGS significantly increased the cell viability, cell migration and the ratios of cells in S phase. CONCLUSION: Our present study demonstrated that the decreased IFIT2 expression could promote the gastric cancer progression and predict poor therapeutic outcomes of the patients.

Serum IL-33 level is a predictor of progression-free survival after chemotherapy.

This study aimed to evaluate the association between of serum IL-33 (sIL-33) level in gastric cancer (GC) patients and progression-free survival (PFS). A total of 62 patients with advanced GC and 32 healthy subjects were enrolled. sIL-33 level was detected in pre-chemotherapy patients, post-chemotherapy patients and healthy subjects, respectively. sIL-33 levels were 131.9 (95% CI 105.9-184.9) pg/mL, 95.1 (95% CI 70.8-140.2) pg/mL and 95.7 (95% CI 73.3-114.3) pg/mL in pre-chemotherapy patients, post-chemotherapy patients and controls, respectively. The sIL-33 level in pre-chemotherapy patients was significantly higher than that in both post-chemotherapy patients and controls (P < 0.001 and P < 0.001, respectively). There was no statistically significant difference between the sIL-33 levels in post-chemotherapy patients and controls (P > 0.05). PFS in patients with the decline extent > 30.1% (median PFS not reached) was statistically significant longer than that (median PFS 7 months, 95% CI 1.569 - 12.431) in patients with the decline extent ≤ 30.1% (P = 0.003). The decline extent of sIL-33 level (> 30.1%) was associated with longer PFS (P = 0.006). Distant metastasis was associated with the decline extent of sIL-33 level (P = 0.034). The decline extent of sIL-33 after chemoresistance could be regarded as a predictor of the PFS of GC patients.

Knockdown of PD-L1 in Human Gastric Cancer Cells Inhibits Tumor Progression and Improves the Cytotoxic Sensitivity to CIK Therapy.

Background/Abstract: PD-L1 has been an important target of cancer immunotherapy. We have showed that in human gastric cancer tissues, over-expression of PD-L1 was significantly associated with cancer progression and patients' postoperative prognoses. However, as of now, how PD-L1 regulates the biological function of gastric cancer cells still remains elusive. METHODS: We constructed the stable PD-L1 knockdown expression gastric cancer cell lines by using RNAi method, and further investigated the changes of biological functions including cell viability, migration, invasion, cell cycle, apoptosis, tumorigenicity in vivo, and the cytotoxic sensitivity to CIK therapy, in contrast to the control cells. RESULTS: In the current study, we demonstrated that the knockdown of PD-L1 expression in human gastric cancer cells could significantly suppress the cell proliferation, migration, invasion, apoptosis, cell cycle, tumorigenicity in vivo and the cytotoxic sensitivity to CIK therapy. CONCLUSION: Our results indicate that PD-L1 contributes towards transformation and progression of human gastric cancer cells, and its intervention could prove to be an important therapeutic strategy against gastric cancer.

Interleukin-33 Expression does not Correlate with Survival of Gastric Cancer Patients.

The aim of the study was to investigate IL-33 expression in gastric cancer (GC) and its association with the clinical characteristics and the prognosis. IL-33 protein in tumor and corresponding adjacent tissues were detected by immunohistochemistry in 179 GC patients and clinical features plus prognostic value were analyzed via Pearson's chi-square test and Kaplan-Meier test in Cox proportional hazards model, respectively. IL-33 protein levels were significantly lower in tumor tissues than adjacent tissues (29.05% vs. 78.77%, χ 2  = 89.05, P < 0.001). The positive rate of IL-33 in the ulcerative type group was the lowest among all groups (P < 0.05). IL-33 levels were correlated with age (P = 0.025) and invasion depth (P = 0.030) while not significantly associated with the overall survival of GC patients. IL-33 expression is associated with age and invasive depth of GC patients but not an independent risk factor of prognosis.

Lower Bmi-1 Expression May Predict Longer Survival of Colon Cancer Patients.

BACKGROUND: This study aimed to investigate the Bmi-1 expression and the clinical significance in colon cancer (CC). PATIENTS AND METHODS: Bmi-1 expression in tumor tissue and the corresponding normal tissue was detected using immunohistological staining. The correlations between Bmi-1 expression and clinicopathological characteristics and the overall survival (OS) time were analyzed. RESULTS: The median H-scores of Bmi-1 in CC tissues and the corresponding tissues were 80.0 (0-270) and 5.0 (0-90), with no statistically significant difference (Z=-13.7, P<0.001). Bmi-1 expression in CC tissues was not statistically correlated with any characteristics. The median OS times for CC patients with high or low Bmi-1 expression were 53.7 months and 44.9 months, respectively, with no statistically significant difference (P = 0.123). The survival rates of patients with low Bmi-1 expression were higher than those of patients with high Bmi-1 expression but the differences were not statistically significant. CONCLUSION: Bmi-1 expression in CC tissue is significantly higher than that in corresponding normal tissue. While there may be a trend towards improved survival, this is not statistically significant.

Assessment of combined expression of B7-H3 and B7-H4 as prognostic marker in esophageal cancer patients.

The co-stimulatory ligands of B7-family have been confirmed to play an important role in negatively regulating the T-cell mediated anti-tumor immunity. In addition, these inhibitory molecules are also aberrantly expressed on various human cancers tissues, and significantly associated with cancer progression and patients' poor prognoses. We have previously reported that B7-H3 and B7-H4 ligands are highly expressed in human esophageal cancer tissues. Herein, we tried to further analyze the value of their combined expression on prognostic prediction for esophageal cancer patients. We found that the combined expression of both B7-H3 and B7-H4 could be used as a valuable risk factor for predicting the prognosis of esophageal cancer patients (P=0.003). Moreover the status of these patients with high expression of both B7-H3 and B7-H4, was positively and significantly associated with the tumor invasion depth (P=0.0414) and TNM stage (P=0.0414). The Cox multivariate proportional hazards regression analysis revealed that the tumor size (P=0.007), the TNM stage (P=0.024) and the status of both B7-H3 and B7-H4 high expression (P=0.011), could be used as an independent risk factor for predicting patients' postoperative prognosis, respectively. In conclusion, our data indicated that the combined application of B7-H3 and B7-H4 expression can be effectively used as a prognostic marker in esophageal cancer patients.

Increased MT2-MMP expression in gastric cancer patients is associated with poor prognosis.

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that contribute to tumorigenesis and metastasis due to their ability to degrade the extracellular matrix (ECM) and basement membrane. In despite of many reports in other solid tumors, the role of membrane type-2 MMP (MT2-MMP) in gastric cancer (GC) remains to be elucidated. The aim of this study was to investigate MT2-MMP expression in human GC tissue microarray (TMA) samples using immunohistochemistry (IHC). We found that MT2-MMP expression in tumor tissues was significantly higher compared to peritumoral tissues (P < 0.01). However, there were no statistically significant differences between MT2-MMP expression and clinicopathological parameters. In addition, univariate and multivariate Cox regression analysis showed GC patients with high MT2-MMP expression have poor overall survival (OS) compared to patients with low MT2-MMP expression (P = 0.013, P = 0.040, respectively). In conclusion, MT2-MMP is involved in GC invasion and metastasis and may serve as an independent prognostic factor for GC patients.