Methyltransferase SETD2 inhibits tumor growth and metastasis via STAT1-IL-8 signaling-mediated epithelial-mesenchymal transition in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a major subtype of non-small-cell lung cancer, which is the leading cause of cancer death worldwide. The histone H3K36 methyltransferase SETD2 has been reported to be frequently mutated or deleted in types of human cancer. However, the functions of SETD2 in tumor growth and metastasis in LUAD has not been well illustrated. Here, we found that SETD2 was significantly downregulated in human lung cancer and greatly impaired proliferation, migration, and invasion in vitro and in vivo. Furthermore, we found that SETD2 overexpression significantly attenuated the epithelial-mesenchymal transition (EMT) of LUAD cells. RNA-seq analysis identified differentially expressed transcripts that showed an elevated level of interleukin 8 (IL-8) in STED2-knockdown LUAD cells, which was further verified using qPCR, western blot, and promoter luciferase report assay. Mechanically, SETD2-mediated H3K36me3 prevented assembly of Stat1 on the IL-8 promoter and contributed to the inhibition of tumorigenesis in LUAD. Our findings highlight the suppressive role of SETD2/H3K36me3 in cell proliferation, migration, invasion, and EMT during LUAD carcinogenesis, via regulation of the STAT1-IL-8 signaling pathway. Therefore, our studies on the molecular mechanism of SETD2 will advance our understanding of epigenetic dysregulation at LUAD progression.

GPC5 suppresses lung cancer progression and metastasis via intracellular CTDSP1/AhR/ARNT signaling axis and extracellular exosome secretion.

Lung cancer is the leading cause of cancer-related death worldwide. Glypican-5 (GPC5) is a member of heparan sulfate proteoglycans, and its biological importance in initiation and progression of lung cancer remains controversial. In the present study, we revealed that GPC5 transcriptionally enhanced the expression of CTDSP1 (miR-26b host gene) via AhR-ARNT pathway, and such up-regulation of CTDSP1 intracellularly contributed to the inhibited proliferation of lung cancer cells. Moreover, exosomes derived from GPC5-overexpressing human lung cancer cells (GPC5-OE-derived exosomes) had an extracellular repressive effect on human lymphatic endothelial cells (hLECs), leading to decreased tube formation and migration. Comparison between GPC5-WT- and GPC5-OE-derived exosomes showed that miR-26b (embedded within introns of CTDSP1 gene) was significantly up-regulated in GPC5-OE-derived exosomes and critical to the influence on hLECs. On the mechanism, we demonstrated that miR-26b transferred into hLECs directly targeted to PTK2 3'-UTR and led to PTK2 down-regulation, resulting in defects in tube formation and migration of hLECs. By uncovering the regulation network among GPC5, miR-26b, miR-26b host gene (CTDSP1), and target gene (PTK2), our findings demonstrated that GPC5 functioned as a tumor suppressor in human lung cancer.

Histone methyltransferase SETD2: a potential tumor suppressor in solid cancers.

Epigenetic regulation plays an important role in the occurrence, development and treatment of malignant tumors; and a great deal of attention has been paid to the histone methylation level in recent years. As a 230-kD epigenetic regulator, the histone H3 lysine 36 histone (H3K36) methyltransferase SETD2 is a key enzyme of the nuclear receptor SET domain-containing (NSD) family, which is associated with a specific hyperphosphorylated domain, a large subunit of RNA polymerase II (RNAPII), named RNAPII subunit B1 (RPB1), and SETD2 which methylates the ly-36 position of dimethylated histone H3 (H3K36me2) to generate trimethylated H3K36 (H3K36me3). SETD2 is involved in various cellular processes, including transcriptional regulation, DNA damage repair, non-histone protein-related functions and some other processes. Great efforts of high-throughput sequencing have revealed that SETD2 is mutated or its function is lost in a range of solid cancers, including renal cancer, gastrointestinal cancer, lung cancer, pancreatic cancer, osteosarcoma, and so on. Mutation, or functional loss, of the SETD2 gene produces dysfunction in corresponding tumor tissue proteins, leading to tumorigenesis, progression, chemotherapy resistance, and unfavorable prognosis, suggesting that SETD2 possibly acts as a tumor suppressor. However, its underlying mechanism remains largely unexplored. In the present study, we summarized the latest advances of effects of SETD2 expression at the mRNA and protein levels in solid cancers, and its potential molecular and cellular functions as well as clinical applications were also reviewed.

Co-mutations of TP53 and KRAS serve as potential biomarkers for immune checkpoint blockade in squamous-cell non-small cell lung cancer: a case report.

BACKGROUND: Unprecedented durable responses are identified in clinical studies to target the signaling of programmed cell death protein-1 (PD-1) as well as its ligand (PD-L1) in patients with squamous-cell non-small cell lung cancer (NSCLC). However, factors predicting the patient subtypes that are responsive to PD-1/PD-L1inhibitors have not been fully understood yet. Biomarkers, like PD-L1 expression, tumor mutational burden(TMB), DNA mismatch repair deficiency (dMMR), and tumor-infiltrating lymphocytes (TILs), have been utilized to select patients responsive to PD-1/PD-L1inhibitors in the clinic, but each of them has limited use. Lung adenocarcinoma patients with a mutation of TP53 or KRAS, particularly those with co-mutations of TP53 and KRAS, can benefit from anti-PD-1 treatment. CASE PRESENTATION: In this study, the co-mutations of TP53 and KRAS in a 64-year-old non-smoking man with squamous-cell NSCLC patient was described using the next-generation sequencing (NGS) technology. The patient was treated with the pembrolizumab combined with gemcitabine as the salvage therapy, and a marked partial response could be attained, which had persisted for over 7 months. CONCLUSION: In addition to testing common driving genes, like EGFR, ALK, ROS1 and BRAF, both TP53, and KRAS should also be considered in advanced or metastatic squamous-cell NSCLC.TP53 and KRAS co-mutations in squamous-cell NSCLC can be a potential factor to assess possible response to PD-1 blockade immunotherapy, but further studies with more cases are needed to confirm the prediction power.

PD-1/PD-L1 pathway in non-small-cell lung cancer and its relation with EGFR mutation.

Immunotherapy has become a crucial modality for non-small-cell lung cancer treatment. Recently, two immune checkpoints, PD-1 and PD-L1, have emerged as important targets for immunotherapy. Their antitumor efficacy has been confirmed by in vitro and in vivo studies. But the correlation between PD-1/PD-L1 expression and EGFR expression was controversial and needs more evidences to support the combination of PD-1/PD-L1 inhibitors and tyrosine kinase inhibitors.

Serum ferritin is elevated in advanced non-small cell lung cancer patients and is associated with efficacy of platinum-based chemotherapy.

AIM: The aim of this study was to determine the expression levels of serum ferritin (SF) and investigate the correlation between SF expression levels and clinical characteristics as well as the efficacy to platinum-based chemotherapy for advanced non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: Electrochemiluminescence method was used to determine the expression levels of SF in the peripheral blood of 46 advanced NSCLC patients and 63 healthy subjects. RESULTS: The expression levels of SF in healthy subjects were significantly lower than those in patients with advanced NSCLC patients (t = -3.279,P = 0.001). There was a statistically significant difference between SF expression levels and distant metastasis, regional lymph node metastasis, respectively (P < 0.05). However, there was no correlation between SF expression levels and sex, age, eastern cooperative oncology group performance status, smoking history, pathological type, tumor location and tumor-node-metastasis stage (All P > 0.05). The overall response rate to platinum-based chemotherapy was 57.1% (12/21) in normal SF expression levels group, which was significantly higher than that was 28% (7/25) in high SF expression levels group (χ² = 3.998,P = 0.046). CONCLUSIONS: SF may be a valuable blood marker for predicting the tumor progression and the efficacy of platinum-based therapies for advanced NSCLC patients.

Report of clinical studies on chronochemotherapy for advanced non-small cell lung cancer in China.

Chronochemotherapy has been proposed as a promising modality to provide timely optimized medication to achieve maximum efficacy with minimum side effect for patients with non-small cell lung cancer for years. We collected the data of 11 clinical studies performed in China with the purpose to compare the difference between chronochemotherapy and traditional chemotherapy. Results showed that chronochemotherapy has a more favorable efficacy and safety than traditional chemotherapy.

Clinical significance of serum ferritin in elderly patients with primary lung carcinoma.

This study determined the levels of serum ferritin (SF) and carcinoembryonic antigen (CEA) in elderly patients with advanced primary lung cancer (PLC), and aimed to investigate the correlation between the SF level and clinical characteristics and compare the positive rates of SF and CEA levels in PLC patients and those in normal subjects. The SF and CEA levels of 69 elderly cases of advanced PLC and 63 elderly controls were determined by electrochemiluminescence method. The correlation between each independent clinicopathological characteristic and levels of SF and CEA was calculated. The positive rates of SF and CEA levels in PLC patients and those in normal subjects were compared. The results revealed that the level of SF in controls was significantly lower than those in patients with advanced LC (145.04 ± 141.77 vs. 293.57 ± 274.95 ng/ml, t = -3.845, P = 0.000). There was a statistically significant difference between SF level and gender, smoking, and regional lymph node metastasis, respectively (P < 0.05). The positive rate of SF combining with CEA was significantly higher than those of SF and CEA alone in patients with advanced PLC. High serum level of SF is helpful for diagnosing PLC in elderly patients and indicates poor prognosis.

CD40 mutant expression and its clinical significance to prognosis in gastric cancer patients.

BACKGROUND: We aimed to detect CD40 mutant expression and evaluate its clinical significance in gastric cancer. METHODS: CD40 mutant expression in 78 cases of gastric cancer tissues, 10 cases of normal gastric tissues, and 10 cases of gastric adenoma tissues by immunohistochemical test. Survival analyses were also performed. RESULTS: The positive CD40 mutant rate in gastric cancer was 55.1% (43/78). No positive CD40 mutant staining was observed in the normal gastric tissue or the gastric adenoma. CD40 mutants expression was significantly correlated with invasive depth, lymph metastasis, and TNM stage (P <0.05). Cases with negative CD40 mutant expression had a significantly longer median survival time than those with positive CD40 mutant expression (40 vs. 14 months, P <0.05). A lower death risk in negative CD40 mutant cases was observed comparing with positive CD40 mutant cases. CONCLUSIONS: Positive CD40 mutant expression suggests a poorer prognosis of gastric cancer cases.

Relationship between glutathione S-transferase P1 (GSTP1), X-ray repair cross complementing group 1 (XRCC1) and 5,10-methylenetetrahydrofolate reductase (5,10-MTHFR) gene polymorphisms and response to chemotherapy in advanced gastric cancer.

BACKGROUND: Our study aimed to investigate the relationship between glutathione S-transferase P1 (GSTP1), 5,10-methylenetetrahydrofolate reductase (5,10-MTHFR) and X-ray repair cross complementing group 1 (XRCC1) gene polymorphisms and the response to chemotherapy in advanced gastric cancer. PATIENTS AND METHODS: 59 cases of advanced gastric cancer were enrolled. All patients were treated with the DCF regimen comprising docetaxel, cisplatin, and 5-fluorouracil. All patients' genotypes regarding GSTP1, XRCC1, and 5,10-MTHFR were analyzed by polymerase chain reaction/ligase detection reaction (PCR-LDR). RESULTS: There were 15 (25.42%) cases of G/G genotype, 21 (35.59%) of G/A genotype, and 23 (38.98%) of A/A genotype for GSTP1, 16 (27.12%) cases of A/A genotype, 18 (30.51%) of G/A genotype, and 25 (42.37%) of G/G genotype for XRCC1, and 21 (35.59%) cases of C/C genotype, 22 (37.29%) of C/T genotype, and 16 (27.12%) of T/T genotype for 5,10-MTHFR. After 2 cycles of chemotherapy, there were 4 cases of complete remission, 14 of partial remission, 19 of stable disease, and 22 of advanced disease, with a total effective rate of 30.51%. Better survival was shown for GSTP1 G/G genotype, XRCC1 A/A genotype, and 5,10-MTHFR T/T genotype (p < 0.05). CONCLUSION: The gene polymorphisms of GSTP1 G/G, XRCC1 A/A, and 5,10-MTHFR T/T have clinical value for predicting the response to the DCF regimen for advanced gastric cancer.

[An epidemiological survey of visceral leishmaniasis in Hamangou coal mine area of Korla City, Xinjiang].

OBJECTIVE: To investigate the epidemiological status of visceral leishmaniasis in Hamangou coal mine area of Korla City of Xinjiang Uygur Autonomous Region. METHODS: Based on a hint of possible existence of patients, a retrospective survey was carried out house by house to find cases with suspected signs/symptoms of the disease. Meanwhile, a survey on current status was conducted, including physical examination (liver and spleen palpation) to those less than 15 years-old, leishmanin skin test and rk39 immunochromatographic strip test for part of the residents. Bone marrow smears were examined for the cases with clinical signs/symptoms and positive rk39 strip test. Sandflies were collected using routine methods in and around the area, identified, and dissected to find infection of promastigotes. RESULTS: Leishmanin skin test was performed in 185 people with a positive rate of 21.1% (39/185), 39 out of 140 local residents who have lived there for more than 6 years showed positive (27.9%), while all residents who have lived less than 6 years and children under 5 years old were negative. Of the 81 children under 15 years old with a negative skin test, one showed positive for rk39 strip test, and leishmania body was found in the bone marrow smear of this case, so confirmed as visceral leishmaniasis. 12 sandflies were identified as Phlebotomus alexandri, and natural infection with promastigotes was found in one sandly. CONCLUSION: The investigation confirms that visceral leishmaniasis is endemic in the Hamangou coal mine area.