Global, regional, and national burden and trends of early-onset tracheal, bronchus, and lung cancer from 1990 to 2019.

BACKGROUND: Tracheal, bronchus, and lung cancer (TBL) is one of the main cancer health problems worldwide, but data on the burden and trends of early-onset tracheal, bronchus, and lung cancer (EO-TBL) are sparse. The aim of the present study was to provide the latest and the most comprehensive burden estimates of the EO-TBL cancer from 1990 to 2019. METHODS: Overall, we used data from the Global Burden of Disease (GBD) study in EO-TBL cancer from 1990 to 2019. Evaluation metrics included incidence, mortality, and disability-adjusted life years (DALYs). The joinpoint regression model was used to analyze the temporal trends. Decomposition analysis was employed to analyze the driving factors for EO-TBL cancer burden alterations. Bayesian age-period-cohort (BAPC) analysis was used to estimate trends in the next 20 years. RESULTS: The global age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), and age-standardized DALYs rate (ASDR) for EO-TBL cancer decreased significantly from 3.95 (95% uncertainty interval [UI]: 3.70-4.24), 3.41 (95% UI: 3.19-3.67), 158.68 (95% UI: 148.04-170.92) in 1990 to 2.82 (95% UI: 2.54-3.09), 2.28 (95% UI: 2.07-2.49), 106.47 (95% UI: 96.83-116.51) in 2019 with average annual percent change (AAPC) of -1.14% (95% confidence interval [CI]: -1.32 to -0.95), -1.37% (95% CI: -1.55 to -1.18), and - 1.35% (95% CI: -1.54 to -1.15) separately. The high and high-middle sociodemographic index (SDI) region had a higher burden of EO-TBL cancer but demonstrated a downward trend. The most prominent and significant upward trends were Southeast and South Asia, Africa, and women in the low SDI and low-middle SDI quintiles. At the regional and national level, there were significant positive correlations between ASDR, ASIR, ASMR, and SDI. Decomposition analysis showed that population growth and aging have driven the increase in the number of incidence, mortality, and DALYs in the global population, especially among the middle SDI quintile and the East Asia region. The BAPC results showed that ASDR, ASIR, and ASMR in women would increase but the male population remained relatively flat over the next 20 years. CONCLUSIONS: Although global efforts have been the most successful and effective in reducing the burden of EO-TBL cancer over the past three decades, there was strong regional and gender heterogeneity. EO-TBL cancer need more medical attention in the lower SDI quintiles and in the female population.

Successful treatment of epidermolysis bullosa pruriginosa by dupilumab.

Epidermolysis bullosa pruriginosa (EBP) is a rare variant of dystrophic epidermolysis bullosa caused by COL7A1 gene mutation. Intense pruritus and nodular prurigo-like lesions are the main features of the disease. To date, the treatment strategies for this condition are not well established. Recent studies have indicated that type 2 inflammation plays a role in the pathophysiology of EBP, suggesting Th2 cytokines could be potential therapeutic targets. In this prospective case series study, we reported three patients with EBP, diagnosed by clinical manifestations, histopathological evaluations, and genetic sequencing, two of whom were treated with dupilumab for 20 weeks. Results showed that the clinical symptoms, pruritus, and quality of life of the patients were significantly improved, as measured by the Epidermolysis Bullosa Disease Activity and Scarring Index, the Visual Analog Scale, and the Children's Dermatology Life Quality Index. Serum immunoglobulin E levels also fell gradually over the 20-week treatment period. Immunotyping of Th1/2/17 cell subsets in peripheral blood by flow cytometry revealed a higher Th2 but parallel Th1 and Th17 cell subsets in patients compared to healthy controls, and a significant decrease in Th2 and an increase in Th17 cells after dupilumab administration. Of note, after 20 weeks of dupilumab treatment, the expression of type VII collagen in the basement membrane of the skin lesion of the patients significantly increased, which was evidenced by immunofluorescence analysis. No treatment-related adverse events were documented. Taken together, targeting type 2 inflammation with dupilumab may be an effective and safe treatment option for EBP.

TBX15/miR-152/KIF2C pathway regulates breast cancer doxorubicin resistance via promoting PKM2 ubiquitination.

BACKGROUND: Chemoresistance is a critical risk problem for breast cancer treatment. However, mechanisms by which chemoresistance arises remains to be elucidated. The expression of T-box transcription factor 15 (TBX-15) was found downregulated in some cancer tissues. However, role and mechanism of TBX15 in breast cancer chemoresistance is unknown. Here we aimed to identify the effects and mechanisms of TBX15 in doxorubicin resistance in breast cancer. METHODS: As measures of Drug sensitivity analysis, MTT and IC50 assays were used in DOX-resistant breast cancer cells. ECAR and OCR assays were used to analyze the glycolysis level, while Immunoblotting and Immunofluorescence assays were used to analyze the autophagy levels in vitro. By using online prediction software, luciferase reporter assays, co-Immunoprecipitation, Western blotting analysis and experimental animals models, we further elucidated the mechanisms. RESULTS: We found TBX15 expression levels were decreased in Doxorubicin (DOX)-resistant breast cancer cells. Overexpression of TBX15 reversed the DOX resistance by inducing microRNA-152 (miR-152) expression. We found that KIF2C levels were highly expressed in DOX-resistant breast cancer tissues and cells, and KIF2C was a potential target of miR-152. TBX15 and miR-152 overexpression suppressed autophagy and glycolysis in breast cancer cells, while KIF2C overexpression reversed the process. Overexpression of KIF2C increased DOX resistance in cancer cells. Furthermore, KIF2C directly binds with PKM2 for inducing the DOX resistance. KIF2C can prevent the ubiquitination of PKM2 and increase its protein stability. In addition, we further identified that Domain-2 of KIF2C played a major role in the binding with PKM2 and preventing PKM2 ubiquitination, which enhanced DOX resistance by promoting autophagy and glycolysis. CONCLUSIONS: Our data identify a new mechanism by which TBX15 abolishes DOX chemoresistance in breast cancer, and suggest that TBX15/miR-152/KIF2C axis is a novel signaling pathway for mediating DOX resistance in breast cancer through regulating PKM2 ubiquitination and decreasing PKM2 stability. This finding suggests new therapeutic target and/or novel strategy development for cancer treatment to overcome drug resistance in the future.

Long noncoding RNA LINC01234 silencing exerts an anti-oncogenic effect in esophageal cancer cells through microRNA-193a-5p-mediated CCNE1 downregulation.

BACKGROUND: Long non-coding RNAs (lncRNAs) are transcribed pervasively in the genome and act to regulate chromatin remodeling and gene expression. Dysregulated lncRNA expression has been reported in many cancers, but the role of lncRNAs in esophageal cancer (EC) has so far remained poorly understood. In this study, we aimed to understand the effect of lncRNA LINC01234 on EC development through competitively binding to microRNA-193a-5p (miR-193a-5p). METHODS: The Gene Expression Omnibus (GEO) database was used for microarray-based EC expression profiling. Gain- and loss-of-function analyses were carried out in human EC-derived Eca-109 and EC9706 cells. Expression analyses of miR-193a-5p, LINC01234, CCNE1, caspase-3, p21, Bax, cyclinD1 and Bcl-2 were performed using RT-qPCR and Western blotting. Cell proliferation, colony formation and apoptosis analyses were carried out using MTT, Hoechst 33258 and flow cytometry assays. A xenograft EC model in nude mice was used to evaluate in vivo tumor growth and CCNE1 expression. RESULTS: Microarray-based analyses revealed that LINC01234 expression was increased in primary EC samples, whereas that of miR-193a-5p was decreased. We found that CCNE1 was a target of miR-193a-5p and that LINC01234, in turn, sponges miR-193a-5p. After treatment with si-LINC01234 or miR-193a-5p mimic, EC cells (Eca-109 and EC9706) exhibited cyclinD1 and Bcl-2 downregulation, and caspase-3, p21, Bax and cleaved caspase-3 upregulation. LINC01234 silencing or miR-193a-5p upregulation resulted in decreased proliferation and colony formation, and increased apoptosis of EC cells. In addition, LINC01234 silencing or miR-193a-5p upregulation resulted in reduced in vivo EC tumor growth and CCNE1 expression in nude mice. CONCLUSIONS: We found that silencing of LINC01234 suppresses EC development by inhibiting CCNE1 through competitively binding to miR-193a-5p, which suggests that LINC01234 may represent a novel target for EC therapy.

Estrogen-induced miR-196a elevation promotes tumor growth and metastasis via targeting SPRED1 in breast cancer.

BACKGROUND: Estrogen plays a critical role in breast cancer (BC) progression through estrogen receptor (ER)-mediated gene regulation. Emerging studies suggest that the malignant progress of BC cells is influenced by the cross talk between microRNAs (miRNAs) and ER-α signaling. However, the mechanism and functional linkage between estrogen and miRNAs remain unclear. METHODS: The expression levels of miR-196a and SPRED1 in BC were tested by qRT-PCR in 46 paired BC and adjacent tissues and by the GEO datasets. The role of miR-196a in estrogen-induced BC development was examined by CCK-8 assay, wound healing assay, Matrigel invasion assay and tumorigenicity assay in nude mice. The binding site of ER-α in miR-196a promoter region was analyzed by ChIP-seq, ChIP assay and luciferase reporter assay. The potential targets of miR-196a in BC cells were explored using the luciferase reporter assay and western blot analysis, and the correlation between miR-196a and SPRED1 was analyzed by Spearman's correlation analysis in BC specimens and GEO dataset. TCGA BRCA data was used to characterize the ESR1 signatures according to MSigDB gene set. RESULTS: The expression levels of miR-196a were higher in ER-positive (ER+) breast tumors compared to ER-negative (ER-) tumor tissue samples. Besides, miR-196a was involved in estrogen-induced BC cell proliferation, migration and invasion. Notably, the up-regulation of miR-196a was mediated by a direct interaction with estrogen receptor α (ER-α) but not estrogen receptor ß (ER-ß) in its promoter region, and miR-196a expression levels were positively correlated to ER-α signature scores. Furthermore, SPRED1 was a new direct target of miR-196a which participated in miR-196a-promoted BC development and was suppressed by ligand-activated ER-α signal pathway. Finally, forced expression of miR-196a induced tumor growth of MCF7 cells, while inhibition of miR-196a significantly suppressed the tumor progress in vivo. CONCLUSIONS: Overall, the identification of estrogen/miR-196a/SPRED1 cascade will shed light on new molecular mechanism of estrogen signaling in BC development and therapy.

Clinical characteristics of severe congenital neutropenia caused by novel ELANE gene mutations.

BACKGROUND: Mutations within the ELANE gene, which encodes human neutrophil elastase, are the most common genetic causes of severe congenital neutropenia (SCN). No cases of SCN have been previously described from a Chinese population. Herein, we describe the clinical, hematologic and molecular characteristics of 7 Chinese SCN cases with novel ELANE mutations. METHODS: Seven Chinese pediatric patients (4 males and 3 females) with suspected SCN were enrolled in this study. Clinical data, peripheral blood, bone marrow and immune function were evaluated for SCN. ELANE genomic DNA and cDNA sequences from patients and potential carriers were analyzed using polymerase chain reaction (PCR) and direct sequencing. RESULTS: All the7 patients experienced recurrent infection (soft tissue, lung, oral cavity) during a period of 120 days. Noninfectious conditions such as anemia and osteopenia were found in most patients, and absolute peripheral neutrophil counts varied. DNA and cDNA sequencing demonstrated that the patients harbored a range of heterozygous ELANE gene mutations, including substitution, deletion, insertion and frame shift alterations. All the mutations had not been reported previously; however, no mutation carriers were identified among the parents or siblings, even in a family with 2 affected offspring. CONCLUSION: SCN cases were identified for the first time in China, and all patients carried novel ELANE mutations. Granulocyte-colony stimulating factor (G-CSF) was an effective treatment for most of the SCN patients and prevented life-threatening bacterial infections.

Prostaglandin E2 receptor EP2 mediates Snail expression in hepatocellular carcinoma cells.

Prostaglandin E2 (PGE2) has been shown to influence cell invasion and metastasis in several types of cancer, including hepatocellular carcinoma (HCC). however, the molecular mechanisms underlying it remain to be further elucidated. Snail, as one of key inducers of epithelial-mesenchymal transition (EMT), plays pivotal roles in HCC invasion and metastasis. The present study was designed to evaluate the possible signaling pathways through which PGE2 regulates Snail protein expression in HCC cell lines. PGE2 markedly enhanced Huh-7 cell invasion and migration ability by upregulating the expression level of Snail protein, and EP2 receptor played an important role in this process. Src, EGFR, Akt and mTOR were all activated and involved in the regulation of snail protein expression. Our findings suggest that PGE2 could upregulate the expression level of Snail protein through the EP2/Src/EGFR/Akt/mTOR pathway in Huh-7 cells, which promotes HCC cell invasion and migration.

Prostaglandin E2 promotes liver cancer cell growth by the upregulation of FUSE-binding protein 1 expression.

Liver cancer is a common human cancer with a high mortality rate and currently there is no effective chemoprevention or systematic treatment. Recent evidence suggests that prostaglandin E(2) (PGE(2)) plays an important role in the occurrence and development of liver cancer. However, the mechanisms through which PGE(2) promotes liver cancer cell growth are not yet fully understood. It has been reported that the increased expression of FUSE-binding protein 1 (FBP1) significantly induces the proliferation of liver cancer cells. In this study, we report that PGE(2) promotes liver cancer cell growth by the upregulation of FBP1 protein expression. Treatment with PGE2 and the E prostanoid 3 (EP3) receptor agonist, sulprostone, resulted in the time-dependent increase in FBP1 protein expression; sulprostone increased the viability of the liver cancer cells. The protein kinase A (PKA) inhibitor, H89, and the adenylate cyclase (AC) inhibitor, SQ22536, inhibited the cell viability accelerated by sulprostone. By contrast, the Gi subunit inhibitor, pertussis toxin (PTX), exhibited no significant effect. Treatment with PGE(2) and sulprostone caused a decrease in JTV1 protein expression, blocked the binding of JTV1 with FBP1, which served as a mechanism for FBP1 degradation, leading to the decreased ubiquitination of FBP1 and the increase in FBP1 protein expression. Furthermore, H89 and SQ22536 prevented the above effects of JTV1 and FBP1 induced by PGE(2) and sulprostone. These findings indicate that the EP3 receptor activated by PGE(2) may couple to Gs protein and activate cyclic AMP (cAMP)-PKA, downregulating the levels of JTV1 protein, consequently inhibiting the ubiquitination of FBP1 and increasing FBP1 protein expression, thus promoting liver cancer cell growth. These observations provide new insights into the mechanisms through which PGE(2) promotes cancer cell growth.

[Study on thoracoabdominal incision for thoracic esophageal carcinoma by rotation position].

OBJECTIVE: To explore the clinical feasibility of thoracoabdominal incision for thoracic esophageal carcinoma by rotation position. METHODS: From January 2004 to December 2007, 126 patients with thoracic esophageal carcinoma performed operation by rotation position. There were 75 males and 51 females aged 46 to 78 years. Tumor was located mid-esophagus in 74 patients, whereas sub-esophagus was present in 52 patients. All patients underwent esophagectomy by rotation position (thoracoabdominal incision). Thoracic and abdominal cavity were exposed well. RESULTS: All operations were completed successful. Anastomotic stoma was located right thorax. The mean number of tow-field lymph node dissection was 25.6. There was no mortality. Postoperative complication include pulmonary complication, incision infection, recurrent laryngeal nerve damage, arrhythmia. The operation time was significantly shortened by rotation position. The number of lymph node dissection was significantly increased. CONCLUSION: The results of this study demonstrated that thoracoabdominal incision for thoracic esophageal carcinoma by rotation position exposes the operation fields clearly and make radical lymphadenectomy thoroughly. Disease-free survival is significantly improved.

GCS induces multidrug resistance by regulating apoptosis-related genes in K562/AO2 cell line.

We have previously shown that the expression of glucosylceramide synthase (GCS) gene in drug-resistant K562/AO2 human leukemia cell was higher than that in drug-sensitive K562 cell, and the sensitivity to adriamycin of K562/AO2 cell was enhanced by inhibiting GCS. It is concluded that the overexpression of GCS gene is one of the reasons which lead to multidrug resistance (MDR) of leukemia cell. Meanwhile, we also found that higher expression of Bcl-2 gene and protein were exhibited in K562/AO2 cell compared with K562 cell. Basing on this, we hypothesized that the high expression of GCS gene which results in MDR of leukemia cell is correlated with Bcl-2 signal transduction. In order to validate the hypothesis, the inhibition of GCS gene in K562/AO2 cell was observed by using chemical suppressor PPMP and siRNA targeted at GCS, and applying RT-PCR and flow cytometry, the expression levels of apoptosis-related gene Bcl-2 and Bax were analyzed before and after inhibiting GCS gene in K562/AO2 cell. The results demonstrated that the gene and protein of Bcl-2 in K562/AO2 cell were both down-regulated significantly after GCS gene being inhibited; however, the Bax mRNA expression had no apparent change in different groups. This suggested that GCS gene may contributed to MDR of human leukemia cell K562/AO2 by Bcl-2 signal transduction.

Prostaglandin E2 upregulates survivin expression via the EP1 receptor in hepatocellular carcinoma cells.

AIMS: Cyclooxygenase-2 (COX-2)-controlled production of prostaglandin E(2) (PGE(2)) has been implicated in cell growth and metastasis in many cancers. Recent studies have found that COX-2 is co-expressed with survivin in many cancers. Survivin is a member of the inhibitor-of-apoptosis protein family. Some COX-2 inhibitors (e.g., celecoxib) can reduce the expression of survivin. However, little is known about the mechanism of PGE(2)-mediated expression of survivin. This study was designed to uncover the effect of PGE(2) on survivin expression in hepatocellular carcinoma cells. MAIN METHODS: The effects of PGE(2) and EP1 agonist on survivin expression were examined in HUH-7 and HepG2 cells. Plasmid transfection and EP1 siRNA were used to regulate the expression of COX-2 and the EP1 receptor protein. KEY FINDINGS: PGE(2) treatment increased survivin expression 2.3-fold. COX-2 overexpression resulted in a similar level of survivin upregulation. However, this effect was suppressed by treatment with celecoxib. EP1 receptor transfection or treatment with a selective EP1 agonist mimicked the effect of PGE(2) treatment. Conversely, the PGE(2)-induced upregulation of survivin was blocked by treatment with a selective EP1 antagonist or siRNA against the EP1 receptor. The phosphorylation of EGFR and Akt were elevated in EP1 agonist-treated cells, and both EGFR and PI3K inhibitors suppressed the upregulation of survivin induced by PGE(2) or EP1 agonist. SIGNIFICANCE: PGE(2) regulates survivin expression in hepatocellular carcinoma cells through the EP1 receptor by activating the EGFR/PI3K pathway. Targeting the PGE(2)/EP1/survivin signaling pathway may aid the development of new therapeutic strategies for both the prevention and treatment of this cancer.

Focal adhesion kinase: important to prostaglandin E2-mediated adhesion, migration and invasion in hepatocellular carcinoma cells.

Prostaglandin E2 has been implicated in cell growth and metastasis in many types of cancers. However, the effects of PGE2 and its mechanism on cell adhesion, migration, and invasion have not been clarified yet. In this study, we found PGE2 treatment significantly increased the cell adhesion, migration, and invasion in hepatocellular carcinoma (HCC) cells. In addition, the effects of PGE2 were found to be associated with focal adhesion kinase (FAK). PGE2 treatment increased the phosphorylation and synthesis of FAK in a dose-dependent manner. RNA interference targeting FAK suppressed PGE2-mediated cell adhesion and migration. Furthermore, the downstream proteins of FAK, paxillin and Erk2, were also activated by PGE2. PGE2 treatment increased the phosphorylation and synthesis of paxillin in a dose-dependent manner. PGE2 treatment also induced the phosphorylation of Erk2. PD98059, the specific inhibitor of MEK, suppressed PGE2-mediated cell adhesion and migration. However, it had no effect on PGE2-induced activation and synthesis of FAK. These results demonstrated that PGE2 greatly induced HCC cell adhesion, migration, and invasion by activating FAK/paxillin/Erk pathway.