Fibroblast growth factor 15, induced by elevated bile acids, mediates the improvement of hepatic glucose metabolism after sleeve gastrectomy.

BACKGROUND: Fibroblast growth factor (FGF) 15/19, which is expressed in and secreted from the distal ileum, can regulate hepatic glucose metabolism in an endocrine manner. The levels of both bile acids (BAs) and FGF15/19 are elevated after bariatric surgery. However, it is unclear whether the increase in FGF15/19 is induced by BAs. Moreover, it remains to be understood whether FGF15/19 elevations contribute to improvements in hepatic glucose metabolism after bariatric surgery. AIM: To investigate the mechanism of improvement of hepatic glucose metabolism by elevated BAs after sleeve gastrectomy (SG). METHODS: By calculating and comparing the changes of body weight after SG with SHAM group, we examined the weight-loss effect of SG. The oral glucose tolerance test (OGTT) test and area under the curve of OGTT curves were used to assess the anti-diabetic effects of SG. By detecting the glycogen content, expression and activity of glycogen synthase as well as the glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (Pepck), we evaluated the hepatic glycogen content and gluconeogenesis activity. We examined the levels of total BA (TBA) together with the farnesoid X receptor (FXR)-agonistic BA subspecies in systemic serum and portal vein at week 12 post-surgery. Then the histological expression of ileal FXR and FGF15 and hepatic FGF receptor 4 (FGFR4) with its corresponding signal pathways involved in glucose metabolism were detected. RESULTS: After surgery, food intake and body weight gain of SG group was decreased compare with the SHAM group. The hepatic glycogen content and glycogen synthase activity was significantly stimulated after SG, while the expression of the key enzyme for hepatic gluconeogenesis: G6Pase and Pepck, were depressed. TBA levels in serum and portal vein were both elevated after SG, the FXR-agonistic BA subspecies: Chenodeoxycholic acid (CDCA), lithocholic acid (LCA) in serum and CDCA, DCA, LCA in portal vein were all higher in SG group than that in SHAM group. Consequently, the ileal expression of FXR and FGF15 were also advanced in SG group. Moreover, the hepatic expression of FGFR4 was stimulated in SG-operated rats. As a result, the activity of its corresponding pathway for glycogen synthesis: FGFR4-Ras-extracellular signal regulated kinase pathway was stimulated, while the corresponding pathway for hepatic gluconeogenesis: FGFR4- cAMP regulatory element-binding protein- peroxisome proliferator-activated receptor γ coactivator-1α pathway was suppressed. CONCLUSION: Elevated BAs after SG induced FGF15 expression in distal ileum by activating their receptor FXR. Furthermore, the promoted FGF15 partly mediated the improving effects on hepatic glucose metabolism of SG.

Efficacy and Safety of Totally Laparoscopic Gastrectomy Compared with Laparoscopic-Assisted Gastrectomy in Gastric Cancer: A Propensity Score-Weighting Analysis.

Objectives: To compare the short- and long-term outcomes of totally laparoscopic gastrectomy (TLG) with laparoscopic-assisted gastrectomy (LAG) in gastric cancer (GC) patients and evaluate the efficacy and safety of TLG. Methods: This retrospective study was based on GC patients who underwent laparoscopic radical gastrectomy in the Qilu Hospital from January 2017 to December 2020. The groups' variables were balanced by using the propensity score-based inverse probability of treatment weighting (PS-IPTW). The primary outcomes were 3-year relapse-free survival (RFS) and 3-year overall survival (OS). Postoperative recovery and complications were the secondary outcomes. Results: A total of 250 GC patients were included in the study. There were no significant differences in baseline and pathological features between the TLG and the LAG groups after the PS-IPTW. TLG took around 30 min longer than LAG, while there were more lymph nodes obtained and less blood loss throughout the procedure. TLG patients had less wound discomfort than LAG patients in terms of short-term prognosis. There were no significant differences between groups in the 3-year RFS rate [LAG vs. TLG: 78.86% vs. 78.00%; hazard ratio (HR) = 1.14, 95% confidence interval (CI), 0.55-2.35; p = 0.721] and the 3-year OS rate (LAG vs. TLG: 78.17% vs. 81.48%; HR = 0.98, 95% CI, 0.42-2.27; p = 0.955). The lymph node staging was found to be an independent risk factor for tumor recurrence and mortality in GC patients with laparoscopic surgery. The subgroup analysis revealed similar results of longer operation time, less blood loss, and wound discomfort in totally laparoscopic distal gastrectomy, while the totally laparoscopic total gastrectomy showed benefit only in terms of blood loss. Conclusion: TLG is effective and safe in terms of short- and long-term outcomes, with well-obtained lymph nodes, decreased intraoperative blood loss, and postoperative wound discomfort, which may be utilized as an alternative to LAG.

Ox-LDL-mediated ILF3 overexpression in gastric cancer progression by activating the PI3K/AKT/mTOR signaling pathway.

BACKGROUND: This study aimed to investigate the relationship of dyslipidemia and interleukin-enhancer binding factor 3 (ILF3) in gastric cancer, and provide insights into the potential application of statins as an agent to prevent and treat gastric cancer. METHODS: The expression levels of ILF3 in gastric cancer were examined with publicly available datasets such as TCGA, and western blotting and immunohistochemistry were performed to determine the expression of ILF3 in clinical specimens. The effects of ox-LDL on expression of ILF3 were further verified with western blot analyses. RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Gene Set Enrichment Analysis (GSEA) pathway analyses were performed to reveal the potential downstream signaling pathway targets of ILF3. The effects of statins and ILF3 on PI3K/AKT/mTOR signaling pathway, cell proliferation, cell cycle, migration and invasion of gastric cancer cells were investigated with Edu assay, flow cytometry and transwell assay. RESULTS: Immunohistochemistry and western blot demonstrated that the positive expression rates of ILF3 in gastric cancer tissues were higher than adjacent mucosa tissues. The ox-LDL promoted the expression of ILF3 in a time-concentration-dependent manner. ILF3 promoted the proliferation, cell cycle, migration and invasion by activating the PI3K/AKT/mTOR signaling pathway. Statins inhibited the proliferation, cell cycle, migration and invasion of gastric cancer by inhibiting the expression of ILF3. CONCLUSIONS: These findings demonstrate that ox-LDL promotes ILF3 overexpression to regulate gastric cancer progression by activating the PI3K/AKT/mTOR signaling pathway. Statins inhibits the expression of ILF3, which might be a new targeted therapy for gastric cancer.

Comparison Between Linear Stapler and Circular Stapler After Laparoscopic-Assisted Distal Gastrectomy in Patients With Gastric Cancer.

Background and Aim: To evaluate the safety and efficacy of laparoscopy distal gastrectomy using a linear stapler compared with a circular stapler in patients with gastric cancer. Methods: We retrospectively reviewed 173 patients who underwent laparoscopic distal gastrectomy for gastric cancer at a single center from January 2018 to December 2020. Patients were categorized into the linear stapler group and the circular stapler group. General data, intraoperative and postoperative outcomes, postoperative pathological results, postoperative complications, and postoperative follow-up in the two groups were compared and analyzed. Results: The operation time (208.76 ± 32.92 vs. 226.69 ± 26.92 min, p < 0.05), anastomosis time (71.87 ± 9.50 vs. 90.56 ± 3.18 min, p < 0.05), time to first flatus (68.60 ± 25.96 vs. 76.16 ± 21.05 h, p < 0.05), time to the first sip of water (3.66 ± 0.61 vs. 4.07 ± 0.77 days, p < 0.05), and time to the first liquid diet (4.43 ± 1.02 vs. 5.03 ± 1.70 days, p < 0.05) were significantly shorter in the linear stapler group. In addition, the highest postoperative body temperature within 3 days (37.4 ± 0.61 vs. 37.7 ± 0.61, p < 0.05) after the operation, white blood cell count (WBC) on the 3rd day (9.07 ± 2.52 vs. 10.01 ± 2.98 × 10∧9/L, p < 0.05), and average gastric tube drainage within 3 days (36.65 ± 24.57 vs. 52.61 ± 37 ml, p < 0.05) were also significantly lower in the linear stapler group. Conclusions: Both circular and linear staplers are safe and feasible for gastrointestinal reconstruction in laparoscopic distal gastrectomy. In contrast, a linear stapler has advantages over a circular stapler in shortening operation time and accelerating the postoperative recovery of patients.

Clinical Application of Indocyanine Green Fluorescence Technology in Laparoscopic Radical Gastrectomy.

Background: This study aimed to observe the application and evaluate the feasibility and safety of indocyanine green (ICG) fluorescence technology in laparoscopic radical gastrectomy (LRG). Methods: Patients who underwent LRG & D2 lymphadenectomy at Qilu Hospital of Shandong University were included between January 2018 and August 2019. According to whether endoscopic injection of ICG was performed, patients were assigned to the ICG group (n=107) and the control group (n=88). The clinicopathologic features, retrieved lymph nodes, postoperative recovery, and follow-up data were compared between the two groups. Results: Baseline characteristics are comparable. The ICG group had a significantly larger number of lymph nodes retrieved (49.55 ± 12.72 vs. 44.44 ± 10.20, P<0.05), shorter total operation time (min) (198.22 ± 13.14 vs. 202.50 ± 9.91, P<0.05), shorter dissection time (min) (90.90 ± 5.34 vs. 93.74 ± 5.35, P<0.05) and less blood loss (ml) (27.51 ± 12.83 vs. 32.02 ± 17.99, P<0.05). The median follow-up time was 29.0 months (range 1.5-43.8 months), and there was no significant difference between the ICG group and the control group in 2-year OS (87.8% vs. 82.9%, P>0.05) or DFS (86.0% vs. 80.7%, P>0.05). Conclusions: ICG fluorescence technology in laparoscopic radical gastrectomy has advantages in LN dissection, operation time, and intraoperative blood loss. The 2-year OS and 2-year DFS rates between the two groups were comparable. In conclusion, ICG fluorescence technology is feasible and safe.

The incidence of second primary cancer in male and female patients with initial colorectal cancer: a SEER population-based study.

BACKGROUND: Second primary cancer (SPC) after primary colorectal cancer (CRC), emerges as a novel challenge for cancer prevention with pronounced differences between female and male patients. METHODS: This was a retrospective study of 140 907 CRC survivors from the surveillance, epidemiology, and end results program database. Competing risk models and nomograms were constructed to predict the risk of SPCs, which were assessed with the C-Index, calibration and decision curve analysis. RESULTS: The 10-year cumulative incidence of SPC was higher in male than in female CRC survivors. The top five common SPCs in female CRC survivors were colorectal, breast, lung and bronchus, corpus and uterus and pancreatic cancers, while in male were prostate, colorectal, lung and bronchus, urinary cancer and melanoma of the skin. Breast and prostate were the most common sites for the development of SPCs after CRC. Older age, stage I and surgery were common risk factors for SPCs in both female and male. The nomogram for predicting the risk of developing SPC-breast cancer in female patients included age, race, site, histology grade, surgery, chemotherapy and stage. However, the model of predicting SPC-prostate cancer in male patients included age, race, site, size, surgery, chemotherapy, radiation and stage. Notably, the nomograms were validated to have a precise discriminative ability, accuracy and clinical effectiveness. CONCLUSIONS: The study surveyed the characteristics of CRC survivors with a particular focus on the incidence of SPC. The models could help supervise the development of a second breast or prostate cancer in female or male CRC survivors.

Lymph node status and its impact on the prognosis of left-sided and right-sided colon cancer: A SEER population-based study.

BACKGROUND: Some significant differences exist between the outcomes of left- and right-sided colon cancer patients. The presence of nodal metastases is a critical prognostic factor, especially in the absence of distant metastasis. Our research studied the lymph nodes status of left- and right-sided colon cancer patients to determine the influence of this factor on prognosis. METHODS: Our data were obtained from the Surveillance, Epidemiology and End Results (SEER) database. We used the chi-square test to analyze the clinicopathological characteristics. The X-tile program was adopted to acquire optimal cutoff points of lymph node index. Kaplan-Meier curves were used to analyze prognosis and multivariate Cox regression models were performed to identify the independent factors associated with survival. Nomograms were built to predict the overall survival of patients, Harrell's C-index and calibration plots were used to validate the nomograms. RESULTS: The study included 189,941 patients with colon cancer without metastasis (left 69,885, right 120,056) between 2004 and 2015. There are more patients with adequate examined lymph nodes in right-sided. Lymph node status in patients with right colon cancer has a more significant impact on the risk of death. LODDS (C-index: 0.583; AIC: 6875.4) was used to assess lymph node status. The nomograms showed that lymph node status was the main factor to predict the outcome in right-sided colon patients. CONCLUSIONS: The influence of lymph node status on predicting prognosis is significantly different between patients with left and right colon cancer without metastasis. The tumor site needs to be considered when lymph node status is used to assess the outcome of patients.

Alternative splicing of mRNA in colorectal cancer: new strategies for tumor diagnosis and treatment.

Alternative splicing (AS) is an important event that contributes to posttranscriptional gene regulation. This process leads to several mature transcript variants with diverse physiological functions. Indeed, disruption of various aspects of this multistep process, such as cis- or trans- factor alteration, promotes the progression of colorectal cancer. Therefore, targeting some specific processes of AS may be an effective therapeutic strategy for treating cancer. Here, we provide an overview of the AS events related to colorectal cancer based on research done in the past 5 years. We focus on the mechanisms and functions of variant products of AS that are relevant to malignant hallmarks, with an emphasis on variants with clinical significance. In addition, novel strategies for exploiting the therapeutic value of AS events are discussed.

A narrative review of the roles of muscle segment homeobox transcription factor family in cancer.

Deregulation of many homeobox genes has been observed in various cancers and has caused functional implications in the tumor progression. In this review, we will focus on the roles of the human muscle segment homeobox (MSX) transcription factor family in the process of tumorigenesis. The MSX transcription factors, through complex downstream regulation mechanisms, are promoters or inhibitors of diverse cancers by participating in cell proliferation, cell invasion, cell metastasis, cell apoptosis, cell differentiation, drug resistance of tumors, maintenance of tumor stemness, and tumor angiogenesis. Moreover, their upstream regulatory mechanisms in cancers may include: gene mutation and chromosome aberration; DNA methylation and chromatin modification; regulation by non-coding RNAs; regulation by other transcription factors and post-translational modification. These mechanisms may provide a better understanding of why MSX transcription factors are abnormally expressed in tumors. Notably, intermolecular interactions and post-translational modification can regulate the transcriptional activity of MSX transcription factors. It is also crucial to know what affects the transcriptional activity of MSX transcription factors in tumors for possible interventions in them in the future. This systematic summary of the regulatory patterns of the MSX transcription factor family may help to further understand the mechanisms involved in transcriptional regulation and also provide new therapeutic approaches for tumor progression.

The Circumferential Resection Margin Is a Prognostic Predictor in Colon Cancer.

Objective: This study aimed to investigate the potential value of circumferential resection margin (CRM) in colon cancer prognostics. Summary Background Data: CRM has been extensively studied as an important prognostic factor in rectal and esophageal cancer, but not in colon cancer. Methods: Data from 6,681 CRM-positive patients and 25,908 CRM-negative patients diagnosed with colon cancer in 2010-2015 were obtained from the Surveillance, Epidemiology, and End Results database. Statistical analysis methods utilized included the chi-square test, Kaplan-Meier estimates, Cox proportional, and X-tile software analyses. Results: After propensity score matching, CRM positivity was found to be negatively related with survival (P < 0.001). X-tile software identified 0 and 30 mm as optimal cutoff values (P < 0.001) for prognosis, which was applicable only in stage II-IV patients. A 20 and 33% risk decrease were observed in patients with CRM between 0 and 30 mm [95% confidence interval (CI) = 0.76-0.84], and larger than 30 mm (95% CI = 0.62-0.71), respectively. Chemotherapy strongly benefited prognosis with a hazard ratio of 0.36 (95% CI = 0.34-0.38) for overall survival (OS). Patients with a CRM value of 0-30 mm seemed to benefit most from chemotherapy compared with other groups. CRM and number of regional lymph nodes are independent risk factors, and the latter is a good substitute for CRM in AJCC stage I patients. Conclusion: CRM positivity is a strong unfavorable survival indicator for colon cancer patients. A better outcome is expected with CRM values larger than 30 mm. This cutoff value only applied to stage II-IV patients. For stage I patients, number of regional lymph nodes is a good substitute to predict survival. Chemotherapy was another favorable prognostic factor, especially for patients with a CRM value between 0 and 30 mm.

Clinicopathological characteristics and prognosis of colorectal mucinous adenocarcinoma and nonmucinous adenocarcinoma: a surveillance, epidemiology, and end results (SEER) population-based study.

BACKGROUND: Mucinous adenocarcinoma (MC) is a rare histological subtype of colorectal adenocarcinoma. Previous studies investigating the prognosis of MC have conflicting results and the proper treatment of MC remains unclear. METHODS: This retrospective study presents the clinicopathological characteristics and prognosis of MC. This cohort study collected data from April 1 through August 01, 2018. This study used data on 107,735 patients with nonmucinous adenocarcinoma (NMC) and 9,494 with MC between 2009 and 2013 from the Surveillance, Epidemiology, and End Results program (SEER). Clinicopathological features were analyzed by chi-square test and survival curves by the Kaplan-Meier method. We used propensity score matching (PSM) to account for potential bias. Logistic regression and Cox proportional hazards models were used to compare and calculate adjusted risks of MC death. RESULTS: MC was more frequent in patients with older age, large tumor size and moderate tumor grade compared with NMC (P<0.001). Five-year survival was lower for MC patients than NMC patients (P<0.001). Older age, later tumor node metastasis (TNM) stage and multiple tumors indicated a poorer prognosis while surgery gave better survival outcomes [hazard ratio (HR) =0.38; 95% confidence interval (CI), 0.33 to 0.44; P<0.001]. Younger age, left-side colon location and early disease stage were associated with better survival after surgery (P<0.001). CONCLUSIONS: Age, TNM stage, tumor number and treatment were indicators of prognosis and surgery gave better survival for MC patients compared with those without surgery. Our study contributes to their clinical treatment.

Hyperbaric oxygen therapy for late radiation-induced tissue toxicity: prospectively patient-reported outcome measures in breast cancer patients.

INTRODUCTION: This study examines patient reported outcome measures of women undergoing hyperbaric oxygen treatment (HBOT) after breast-conserving therapy. METHOD: Included were 57 women treated with HBOT for late radiation-induced tissue toxicity (LRITT) referred in the period January 2014-December 2015. HBOT consisted of (on average) 47 sessions. In total, 80 min of 100 % O2 was administered under increased pressure of 2.4 ATA. Quality of life was assessed before and after treatment using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-BR23, and a NRS pain score. RESULTS: Fifty-seven women were available for evaluation before and after treatment. Before HBOT, patients had severe complaints of pain in the arm/shoulder (46 %), swollen arm/hand (14 %), difficulty to raise arm or move it sideways (45 %), pain in the area of the affected breast (67 %), swollen area of the affected breast (45 %), oversensitivity of the affected breast (54 %), and skin problems on/in the area of the affected breast (32 %); post HBOT, severe complaints were still experienced in 17, 7, 22, 15, 13, 15, and 11 % of the women, respectively. Differences were all significant. The NRS pain score improved at least 1 point (range 0-10) in 81 % of the patients (p < 0.05). CONCLUSION: In these breast cancer patients treated with HBOT for LRITT, the patient-reported outcomes were positive and improvements were observed. HBOT was a well-tolerated treatment for LRITT and its side-effects were both minimal and reversible.

Disruption of Sirtuin 1-Mediated Control of Circadian Molecular Clock and Inflammation in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death, and it is characterized by abnormal inflammation and lung function decline. Although the circadian molecular clock regulates inflammatory responses, there is no information available regarding the impact of COPD on lung molecular clock function and its regulation by sirtuin 1 (SIRT1). We hypothesize that the molecular clock in the lungs is disrupted, leading to increased inflammatory responses in smokers and patients with COPD and its regulation by SIRT1. Lung tissues, peripheral blood mononuclear cells (PBMCs), and sputum cells were obtained from nonsmokers, smokers, and patients with COPD for measurement of core molecular clock proteins (BMAL1, CLOCK, PER1, PER2, and CRY1), clock-associated nuclear receptors (REV-ERBα, REV-ERBß, and RORα), and SIRT1 by immunohistochemistry, immunofluorescence, and immunoblot. PBMCs were treated with the SIRT1 activator SRT1720 followed by LPS treatment, and supernatant was collected at 6-hour intervals. Levels of IL-8, IL-6, and TNF-α released from PBMCs were determined by ELISA. Expression of BMAL1, PER2, CRY1, and REV-ERBα was reduced in PBMCs, sputum cells, and lung tissues from smokers and patients with COPD when compared with nonsmokers. SRT1720 treatment attenuated LPS-mediated reduction of BMAL1 and REV-ERBα in PBMCs from nonsmokers. Additionally, LPS differentially affected the timing and amplitude of cytokine (IL-8, IL-6, and TNF-α) release from PBMCs in nonsmokers, smokers, and patients with COPD. Moreover, SRT1720 was able to inhibit LPS-induced cytokine release from cultured PBMCs. In conclusion, disruption of the molecular clock due to SIRT1 reduction contributes to abnormal inflammatory response in smokers and patients with COPD.

Serotonin and corticosterone rhythms in mice exposed to cigarette smoke and in patients with COPD: implication for COPD-associated neuropathogenesis.

The circadian timing system controls daily rhythms of physiology and behavior, and disruption of clock function can trigger stressful life events. Daily exposure to cigarette smoke (CS) can lead to alteration in diverse biological and physiological processes. Smoking is associated with mood disorders, including depression and anxiety. Patients with chronic obstructive pulmonary disease (COPD) have abnormal circadian rhythms, reflected by daily changes in respiratory symptoms and lung function. Corticosterone (CORT) is an adrenal steroid that plays a considerable role in stress and anti-inflammatory responses. Serotonin (5-hydroxytryptamine; 5HT) is a neurohormone, which plays a role in sleep/wake regulation and affective disorders. Secretion of stress hormones (CORT and 5HT) is under the control of the circadian clock in the suprachiasmatic nucleus. Since smoking is a contributing factor in the development of COPD, we hypothesize that CS can affect circadian rhythms of CORT and 5HT secretion leading to sleep and mood disorders in smokers and patients with COPD. We measured the daily rhythms of plasma CORT and 5HT in mice following acute (3 d), sub-chronic (10 d) or chronic (6 mo) CS exposure and in plasma from non-smokers, smokers and patients with COPD. Acute and chronic CS exposure affected both the timing (peak phase) and amplitude of the daily rhythm of plasma CORT and 5HT in mice. Acute CS appeared to have subtle time-dependent effects on CORT levels but more pronounced effects on 5HT. As compared with CORT, plasma 5HT was slightly elevated in smokers but was reduced in patients with COPD. Thus, the effects of CS on plasma 5HT were consistent between mice and patients with COPD. Together, these data reveal a significant impact of CS exposure on rhythms of stress hormone secretion and subsequent detrimental effects on cognitive function, depression-like behavior, mood/anxiety and sleep quality in smokers and patients with COPD.

Hypoxia inducible factor 3α plays a critical role in alveolarization and distal epithelial cell differentiation during mouse lung development.

Lung development occurs under relative hypoxia and the most important oxygen-sensitive response pathway is driven by Hypoxia Inducible Factors (HIF). HIFs are heterodimeric transcription factors of an oxygen-sensitive subunit, HIFα, and a constitutively expressed subunit, HIF1ß. HIF1α and HIF2α, encoded by two separate genes, contribute to the activation of hypoxia inducible genes. A third HIFα gene, HIF3α, is subject to alternative promoter usage and splicing, leading to three major isoforms, HIF3α, NEPAS and IPAS. HIF3α gene products add to the complexity of the hypoxia response as they function as dominant negative inhibitors (IPAS) or weak transcriptional activators (HIF3α/NEPAS). Previously, we and others have shown the importance of the Hif1α and Hif2α factors in lung development, and here we investigated the role of Hif3α during pulmonary development. Therefore, HIF3α was conditionally expressed in airway epithelial cells during gestation and although HIF3α transgenic mice were born alive and appeared normal, their lungs showed clear abnormalities, including a post-pseudoglandular branching defect and a decreased number of alveoli. The HIF3α expressing lungs displayed reduced numbers of Clara cells, alveolar epithelial type I and type II cells. As a result of HIF3α expression, the level of Hif2α was reduced, but that of Hif1α was not affected. Two regulatory genes, Rarß, involved in alveologenesis, and Foxp2, a transcriptional repressor of the Clara cell specific Ccsp gene, were significantly upregulated in the HIF3α expressing lungs. In addition, aberrant basal cells were observed distally as determined by the expression of Sox2 and p63. We show that Hif3α binds a conserved HRE site in the Sox2 promoter and weakly transactivated a reporter construct containing the Sox2 promoter region. Moreover, Hif3α affected the expression of genes not typically involved in the hypoxia response, providing evidence for a novel function of Hif3α beyond the hypoxia response.

Congenital lung lesions--underlying molecular mechanisms.

Congenital lung lesions comprise a broad spectrum of rare but clinically significant developmental abnormalities, including congenital cystic adenomatoid malformation, bronchopulmonary sequestrations, congenital lobar emphysema, and bronchogenic cysts, which are commonly surgically treated. Although the terms congenital cystic adenomatoid malformation, bronchopulmonary sequestrations, congenital lobar emphysema, and bronchogenic cysts are entrenched in clinical usage and comfortably correspond to rigid pathologic definitions, there is a considerable overlap in the findings. Disregarding the controversy about lesion nomenclature and classification, it is widely accepted that congenital lung lesions result from perturbations in lung and airway embryogenesis. It is generally accepted that both place (level in the tracheobronchial tree) and timing (gestational age) of the embryologic insult correlates with the type of lesion and histopathology that is manifested. The objective of this review is to briefly review normal lung development and to analyze the known molecular mechanisms underlying those diseases.