Pleural mesothelioma from fluoro-edenite exposure: PACAP and PAC1 receptor. A preliminary report.

Pleural mesothelioma is a devastating malignancy primarily associated with asbestos exposure. However, emerging evidence suggests that exposure to fluoro-edenite fibers, a naturally occurring mineral fiber, can also lead to the development of pleural mesothelioma. In this study, based on the hypothesis that pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP-preferring receptor (PAC1R) expressions could be dysregulated in pleural mesothelioma samples and that they could potentially act as diagnostic or prognostic biomarkers, we aimed to investigate the immunohistochemical expression of PACAP and PAC1R in pleural biopsies from patients with pleural mesothelioma exposed to fluoro-edenite fibers. A total of 12 patients were included in this study, and their biopsies were processed for immunohistochemical analysis to evaluate the expression of PACAP and its receptor. The study revealed a correlation between the overexpression of PACAP and PAC1R and shorter overall survival in patients with malignant mesothelioma. These findings suggest that PACAP and PAC1R expression levels could serve as potential prognostic biomarkers for malignant mesothelioma. Furthermore, the immunohistochemical analysis of PACAP and PAC1R may provide valuable information for clinicians to guide therapeutic decisions and identify patients with poorer prognosis.

HK2 and LDHA upregulation mediate hexavalent chromium-induced carcinogenesis, cancer development and prognosis through miR-218 inhibition.

Hexavalent chromium [Cr(VI)] is one of the most common environmental contaminants due to its tremendous industrial applications, but its effects and mechanism remain to be investigated. Our previous studies showed that Cr(VI) exposure caused malignant transformation and tumorigenesis. This study showed that glycolytic proteins HK2 and LDHA levels were statistically significant changed in blood samples of Cr(VI)-exposed workers and in Cr-T cells compared to the control subjects and parental cells. HK2 and LDHA knockdown inhibited cell proliferation and angiogenesis, and higher HK2 and LDHA expression levels are associated with advanced stages and poor prognosis of lung cancer. We found that miR-218 levels were significantly decreased and miR-218 directly targeted HK2 and LDHA for inhibiting their expression. Overexpression of miR-218 inhibited glucose consumption and lactate production in Cr-T cells. Further study found that miR-218 inhibited tumor growth and angiogenesis by decreasing HK2 and LDHA expression in vivo. MiR-218 levels were negatively correlated with HK2 and LDHA expression levels and cancer development in human lung and other cancers. These results demonstrated that miR-218/HK2/LDHA pathway is vital for regulating Cr(VI)-induced carcinogenesis and human cancer development.

Fine particulate matter (PM2.5) promotes chemoresistance and aggressive phenotype of A549 lung cancer cells.

Lung cancer is one of the most aggressive malignancies with a high mortality rate. In large cities, particulate matter (PM) is a common air pollutant. High PM levels with aerodynamic size ≤2.5 µm (PM2.5) associates with lung cancer incidence and mortality. In this work, we explored PM2.5 effects on the behavior of lung cancer cells. To this, we chronically exposed A549 cells to increasing PM2.5 concentrations collected in México City, then evaluating cell proliferation, chemoresponse, migration, invasion, spheroid formation, and P-glycoprotein and N-cadherin expression. Chronic PM2.5 exposure from 1 µg/cm2 stimulated A549 cell proliferation, migration, and chemoresistance and upregulated P-glycoprotein and N-cadherin expression. PM2.5 also induced larger multicellular tumor spheroids (MCTS) and less disintegration compared with control cells. Therefore, these results indicate lung cancer patients exposed to airborne PM2.5 as urban pollutant could develop more aggressive tumor phenotypes, with increased cell proliferation, migration, and chemoresistance.

Trends in work-related respiratory diseases attributed to nickel, chromium and cobalt in the UK: descriptive findings from The Health and Occupation Research (THOR) network 1996-2019.

BACKGROUND: Occupational exposure to metals can be associated with respiratory diseases which can adversely affect the individual's health, finances and employment. Despite this, little is known about the incidence of these respiratory conditions over prolonged periods of time. AIMS: This study aimed to investigate the trends in the incidence of work-related respiratory diseases attributed to nickel, chromium and cobalt in the UK. METHODS: Cases of occupational respiratory diseases caused by nickel, chromium or cobalt reported to Surveillance of Work-related and Occupational Respiratory Disease (SWORD), the UK-based surveillance scheme between 1996 and 2019 (inclusive), were extracted and grouped into six 4-year time periods. Cases were characterised by causative metal exposure, occupational and industrial sector. Incidence rates diseases (adjusted for physician participation and response rate) were calculated using ONS employment data. RESULTS: Of cases reported to SWORD during the study period, 1% (173 actual cases) of respiratory problems were attributed to nickel, chromium or cobalt. Diagnoses of asthma compromised the largest proportion of diagnoses (74.4%), followed by lung cancer (8.9%) and pneumoconiosis (6.7%). Cases had a mean age of 47 years (SD 13); 93% were men. The annual incidence fell from 1.6 per million employed in the first 4-year period, to 0.2 in the most recent period. CONCLUSIONS: Over 24 years, a decline in the incidence of metal-related occupational respiratory diseases was observed in the UK. This could be attributed to improvements in working conditions which resulted in reduced metal exposure but could also be due to closure of industries that might have generated case returns.

EIF4A3 modulated circ_000999 promotes epithelial-mesenchymal transition in cadmium-induced malignant transformation through the miR-205-5p/ZEB1 axis.

Cadmium (Cd) is an accumulative toxic metal which poses a serious threat to human health, even in trace amounts. One of the most important steps in the pathophysiology of lung cancer (LC) is the epithelial-mesenchymal transition (EMT). In this investigation, a cell malignant transformation model was established by exposing human bronchial epithelial cells (16HBE) to a low dose of Cd for 30 weeks, after which a highly expressed circular RNA (circ_000999) was identified. Cd-induced EMT was clearly observed in rat lungs and 16HBE cells, which was further enhanced following circ_000999-overexpression. Furthermore, upregulated EIF4A3 interacted with the parental gene AGTPBP1 to promote high expression of circ_000999. Subsequent experiments confirmed that circ_000999 could regulate the EMT process by competitively binding miR-205-5p and inhibiting its activity, consequently upregulating expression of zinc finger E-box binding protein 1 (ZEB1). Importantly, the circ_000999 expression level in LC tissues was significantly increased, exhibiting a strong correlation with EMT indicators. Overall, these findings provide a new objective and research direction for reversing lung EMT and subsequent treatment and prevention of LC.

ß-Lapachone, an NQO1 bioactivatable drug, prevents lung tumorigenesis in mice.

Lung cancer is one of the most lethal cancers with high incidence worldwide. The prevention of lung cancer is of great significance to reducing the social harm caused by this disease. An in-depth understanding of the molecular changes underlying precancerous lesions is essential for the targeted chemoprevention against lung cancer. Here, we discovered an increased NQO1 level over time within pulmonary premalignant lesions in both the KrasG12D-driven and nicotine-derived nitrosamine ketone (NNK)-induced mouse models of lung cancer, as well as in KrasG12D-driven and NNK-induced malignant transformed human bronchial epithelial cells (BEAS-2B and 16HBE). This suggests a potential correlation between the NQO1 expression and lung carcinogenesis. Based on this finding, we utilized ß-Lapachone (ß-Lap), an NQO1 bioactivatable drug, to suppress lung tumorigenesis. In this study, the efficacy and safety of low-dose ß-Lap were demonstrated in preventing lung tumorigenesis in vivo. In conclusion, our study suggests that long-term consumption of low-dose ß-Lap could potentially be an effective therapeutic strategy for the prevention of lung premalignant lesions. However, further studies and clinical trials are necessary to validate our findings, determine the safety of long-term ß-Lap usage in humans, and promote the use of ß-Lap in high-risk populations.

A nationwide case-referent study on elevated risks of adenocarcinoma lung cancer by long-term PM2.5 exposure in Taiwan since 1997.

BACKGROUND: The effects of long-term PM2.5 exposures since 1968 on adenocarcinoma lung cancer (AdLC) were not studied before. METHODS: This case-referent study used nationwide cancer registry data since 1997 and air pollution data since 1968 in Taiwan to estimate risks of 30-year PM2.5 exposures on AdLC. Cases were all AdLC, while references were all non-AdLC. Individuals' 30-year PM2.5 exposures were estimated by PM2.5 levels at their residence for 30 years prior their diagnosis dates. We applied multiple logistic regression analyses to estimate PM2.5 exposures on incidence rate ratios (IRRs) between cases and references, adjusting for sex, age, smoking, cancer stage, and EGFR mutation. RESULTS: Elevation in annual ambient PM2.5 concentrations since 1968 were associated with increase in annual age-adjusted AdLC incidence since 1997. AdLC incidences were higher among females, nonsmokers, the elderly aged above 65, cases of stages IIIB to IV, and EGFR mutation. Study subjects' PM2.5 exposures averaged at 33.7 ± 7.4 µg/m3 with 162 ± 130 high PM2.5 pollution days over 30 years. Multiple logistic models showed an increase in 10 µg/m3 of PM2.5 exposures were significantly associated with 1.044 of IRR between all AdLC and all non-AdLC cases during 2011-2020. Our models also showed that females and nonsmokers and adults less than 65 years had higher IRRs than their respective counterparts. Restricted analyses showed similar effects of PM2.5 exposures on IRRs between stage 0-IIIA and IIIB-IV cases and between EGFR+ and EGFR- cases. CONCLUSIONS: Long-term exposures to PM2.5 over 30 years were associated with elevated risks of AdLC against non-AdLC, regardless of gender, age, smoking status, cancer stage, or EGFR mutation.

An In Vitro Examination of Whether Kratom Extracts Enhance the Cytotoxicity of Low-Dose Doxorubicin against A549 Human Lung Cancer Cells.

Doxorubicin is an effective chemotherapeutic agent in the treatment of solid hematological and non-hematological carcinoma. However, its long-term usage could result in side effects, such as cardiomyopathy, chronic heart failure, neurotoxicity and cancer cell resistance. In this study, we reported the sensitivity enhancement of A549 human lung cancer cells on doxorubicin at a low dose (0.1 ppm) in combination with 10-60 ppm of crude and alkaloid extracts derived from the leaves of Kratom (Mitragyna speciosa (Korth.) Havil. Rubiaceae). A549 cancer cell lines were insensitive to the crude extract containing low mitragynine (MG) (4-5%), while these cells were moderately inhibited by the alkaloid extract containing 40-45% MG (IC50 of 48-55 ppm). The alkaloid extract was found to inhibit A549 cancer cells via apoptosis as suggested by the higher relative fluorescence intensity with Annexin compared to that in propidium iodide (PI), i.e., a positive Annexin and a negative PI. The combination of crude extract and doxorubicin sensitized A549 cancer cells to doxorubicin by 1.3 to 2.4 times, while the combination with the alkaloid induced a 2.6- to 3.4-fold increase in sensitivity. The calculated combination index (CI) for doxorubicin with the crude and alkaloid extracts was 0.6 and 0.3, respectively, showing potential synergistic combinations to reduce the level of dosage of doxorubicin used in chemotherapy. In addition, the synergistic enhancement effect of crude extract on the cytotoxic activity of doxorubicin provides insights into the plausibility of non-alkaloids to influence the biological activities of Kratom.

Complex Genomic Rearrangement Patterns in Malignant Pleural Mesothelioma due to Environmental Asbestos Exposure.

Malignant pleural mesothelioma (MPM) is a rare type of cancer, and its main risk factor is exposure to asbestos. Accordingly, our knowledge of the genomic structure of an MPM tumor is limited when compared to other cancers. In this study, we aimed to characterize complex genomic rearrangement patterns and variations to better understand the genomics of MPM tumors. We comparatively scanned 3 MPM tumor genomes by Whole-Genome Sequencing and High-Resolution SNP array. We also used various computational algorithms to detect both CNAs and complex chromosomal rearrangements. Genomic data obtained from each bioinformatics tool are interpreted comparatively to better understand CNAs and cancer-related Nucleotide variations in MPM tumors. In patients 1 and 2, we found pathogenic nucleotide variants of BAP1, RB1, and TP53. These two MPM genomes exhibited a highly rearranged chromosomal rearrangement pattern resembling Chromomanagesis particularly in the form of Chromoanasynthesis. In patient 3, we found nucleotide variants of important cancer-related genes, including TGFBR1, KMT2C, and PALLD, to have lower chromosomal rearrangement complexity compared with patients 1 and 2. We also detected several actionable nucleotide variants including XRCC1, ERCC2. We also discovered the SKA3-DDX10 fusion in two MPM genomes, which is a novel finding for MPM. We found that MPM genomes are very complex, suggesting that this highly rearranged pattern is strongly related to driver mutational status like BAP1, TP53 and RB1.

Transcriptomic analysis reveals particulate hexavalent chromium regulates key inflammatory pathways in human lung fibroblasts as a possible mechanism of carcinogenesis.

Hexavalent chromium [Cr(VI)] is considered a major environmental health concern and lung carcinogen. However, the exact mechanism by which Cr(VI) causes lung cancer in humans remains unclear. Since several reports have demonstrated a role for inflammation in Cr(VI) toxicity, the present study aimed to apply transcriptomics to examine the global mRNA expression in human lung fibroblasts after acute (24 h) or prolonged (72 and 120 h) exposure to 0.1, 0.2 and 0.3 µg/cm2 zinc chromate, with a particular emphasis on inflammatory pathways. The results showed Cr(VI) affected the expression of multiple genes and these effects varied according to Cr(VI) concentration and exposure time. Bioinformatic analysis of RNA-Seq data based on the Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and MetaCore databases revealed multiple inflammatory pathways were affected by Cr(VI) treatment. qRT-PCR data corroborated RNA-Seq findings. This study showed for the first time that Cr(VI) regulates key inflammatory pathways in human lung fibroblasts, providing novel insights into the mechanisms by which Cr(VI) causes lung cancer.

Sodium-glucose cotransporter-2 inhibitors and the risk of lung cancer among patients with type 2 diabetes.

We sought to determine whether the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors is associated with a decreased risk of incident lung cancers among patients with type 2 diabetes. We assembled a new-user, active comparator cohort of SGLT-2 inhibitor and dipeptidyl peptidase-4 (DPP-4) inhibitor users using the United Kingdom Clinical Practice Research Datalink. We fit Cox proportional hazards models with propensity score fine stratification weighting to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for incident lung cancer. Crude incidence rates were 0.94 per 1000 person-years among 69 675 SGLT-2 inhibitor users followed for a median of 2.4 years and 1.45 per 1000 person-years among 151 495 DPP-4 inhibitor users followed for a median of 3.7 years. No reduced short-term risk of lung cancer was observed among SGLT-2 inhibitor users after weighting (HR 0.96, 95% CI 0.77-1.21). Further research with a longer follow-up period may be warranted.

Outcomes of patients with advanced epithelial growth factor receptor mutant lung cancer treated with first-line osimertinib who would not have met the eligibility criteria for the FLAURA clinical trial.

OBJECTIVES: Osimertinib is largely used as first-line therapy for metastatic epithelial growth factor receptor (EGFR) mutant lung cancers based on the FLAURA clinical trial. Real-world patient outcomes often differ from clinical trial outcomes. This study evaluated the efficacy of first-line osimertinib in patients treated in British Columbia (BC), Canada. Furthermore, we compared the outcomes of patients who would and would not have been eligible for the original FLAURA trial. METHODS: Consecutive patients receiving first-line osimertinib for metastatic EGFR exon19 or L858R lung cancer were identified using the BC Cancer Pharmacy Database. Patient eligibility for the FLAURA clinical trial were retrospectively reviewed based on the following criteria: ECOG ≥ 2, symptomatic brain metastases or on steroids, hemoglobin < 90 g/L, platelets < 100x109/L, or a creatinine clearance < 50 mL/min. mOS was assessed for the entire population and compared between patients who would have been eligible and ineligible for FLAURA. RESULTS: From January 2020 to October 2021, 311 patients received first-line osimertinib; 44 % (137/311) were deemed FLAURA ineligible, predominantly due to low ECOG (n = 120). After a median follow-up of 26.5 months, the mOS for the entire cohort was 27.4 months (95 %CI 23.8-30.1). The mOS for ineligible patients was 18 months shorter than eligible patients (15.8 vs 34.2, p < 0.001). Ineligible patients had higher rates of de novo stage IV disease, higher rates of stage IVB disease, and more sites of disease than eligible patients. CONCLUSION: In this real-world population, nearly half of patients would have been ineligible for FLAURA. The mOS was one year shorter than reported in FLAURA. However, patients who would have been eligible for the FLAURA clinical trial had similar OS to patients enrolled in FLAURA. Trial ineligible patients had a higher burden of disease at baseline which may have led to inferior outcomes. Further research is needed to improve outcomes in these patients.

Final results of urelumab, an anti-CD137 agonist monoclonal antibody, in combination with cetuximab or nivolumab in patients with advanced solid tumors.

BACKGROUND: Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors. METHODS: CA186-018: Patients with metastatic colorectal cancer or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated in a dose-evaluation phase with urelumab 0.1 mg/kg (urelumab-0.1) every 3 weeks (Q3W)+cetuximab 250 mg/m2 (cetuximab-250) weekly; and in a dose-expansion phase with urelumab 8 mg flat dose (urelumab-8) Q3W+cetuximab-250 weekly. CA186-107: The dose-escalation phase included patients with previously treated advanced solid tumors (or treated or treatment-naive melanoma); patients received urelumab 3 mg flat dose (urelumab-3) or urelumab-8 every 4 weeks+nivolumab 3 mg/kg (nivolumab-3) or 240 mg (nivolumab-240) every 2 weeks. In the expansion phase, patients with melanoma, non-small cell lung cancer, or SCCHN were treated with urelumab-8+nivolumab-240. Primary endpoints were safety and tolerability, and the secondary endpoint included efficacy assessments. RESULTS: CA186-018: 66 patients received study treatment. The most frequent treatment-related adverse events (TRAEs) were fatigue (75%; n=3) with urelumab-0.1+cetuximab-250 and dermatitis (45%; n=28) with urelumab-8+cetuximab-250. Three patients (5%) discontinued due to TRAE(s) (with urelumab-8+cetuximab-250). One patient with SCCHN had a partial response (objective response rate (ORR) 5%, with urelumab-8+cetuximab-250).CA186-107: 134 patients received study treatment. Fatigue was the most common TRAE (32%; n=2 with urelumab-3+nivolumab-3; n=1 with urelumab-8+nivolumab-3; n=40 with urelumab-8+nivolumab-240). Nine patients (7%) discontinued due to TRAE(s) (n=1 with urelumab-3+nivolumab-3; n=8 with urelumab-8+nivolumab-240). Patients with melanoma naive to anti-PD-1 therapy exhibited the highest ORR (49%; n=21 with urelumab-8+nivolumab-240). Intratumoral gene expression in immune-related pathways (CD3, CD8, CXCL9, GZMB) increased on treatment with urelumab+nivolumab. CONCLUSIONS: Although the addition of urelumab at these doses was tolerable, preliminary response rates did not indicate an evident additive benefit. Nevertheless, the positive pharmacodynamics effects observed with urelumab and the high response rate in treatment-naive patients with melanoma warrant further investigation of other anti-CD137 agonist agents for treatment of cancer. TRIAL REGISTRATION NUMBERS: NCT02110082; NCT02253992.

Associations between urinary concentrations of benzothiazole, benzotriazole, and their derivatives and lung cancer: A nested case-control study.

Benzothiazole (BTH), benzotriazole (BTR), and their respective derivatives (BTHs and BTRs) are emerging environmental pollutants with widespread human exposure and oncogenic potential. Studies have demonstrated adverse effects of exposure to certain BTHs and BTRs on the respiratory system. However, no study has examined the associations between exposure to BTHs and BTRs and lung cancer risk. We aimed to examine the associations between urinary concentrations of BTHs and BTRs and the risk of lung cancer in the general population from Quzhou, China. We conducted a nested case-control study in an ongoing prospective Quzhou Environmental Exposure and Human Health (QEEHH) cohort, involving 20, 694 participants who provided urine samples during April 2019-July 2020. With monthly follow-up until November 2022, 212 lung cancer cases were recruited and 1:1 matched with healthy controls based on age and sex. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) of lung cancer risk associated with urinary BTHs and BTRs concentrations using conditional logistic regression models after controlling for potential covariates. We also examined effect modification by several covariates, including sex, socioeconomic status, smoking status, alcohol consumption, and dietary habit. Creatinine-corrected urinary BTH and 2-hydroxy-benzothiazole (2-OH-BTH) levels were significantly associated with the risk of lung cancer, after adjusting for a variety of covariates. Participants in the highest quartile of BTH had a 95% higher risk of lung cancer, compared with those in the lowest quartile (adjusted OR = 1.95, 95% CI: 1.08-3.49; p for trend = 0.01). Participants with higher levels of urinary 2-OH-BTH had an 83% higher risk of lung cancer than those with lower levels (adjusted OR = 1.83, 95% CI: 1.16-2.88; p for trend = 0.01). Exposure to elevated levels of BTH and 2-OH-BTH may be associated with an increased risk of lung cancer. These associations were not modified by socio-demographic characteristics.

Procedural application of mode-of-action and human relevance analysis: styrene-induced lung tumors in mice.

Risk assessment of human health hazards has traditionally relied on experiments that use animal models. Although exposure studies in rats and mice are a major basis for determining risk in many cases, observations made in animals do not always reflect health hazards in humans due to differences in biology. In this critical review, we use the mode-of-action (MOA) human relevance framework to assess the likelihood that bronchiolar lung tumors observed in mice chronically exposed to styrene represent a plausible tumor risk in humans. Using available datasets, we analyze the weight-of-evidence 1) that styrene-induced tumors in mice occur through a MOA based on metabolism of styrene by Cyp2F2; and 2) whether the hypothesized key event relationships are likely to occur in humans. This assessment describes how the five modified Hill causality considerations support that a Cyp2F2-dependent MOA causing lung tumors is active in mice, but only results in tumorigenicity in susceptible strains. Comparison of the key event relationships assessed in the mouse was compared to an analogous MOA hypothesis staged in the human lung. While some biological concordance was recognized between key events in mice and humans, the MOA as hypothesized in the mouse appears unlikely in humans due to quantitative differences in the metabolic capacity of the airways and qualitative uncertainties in the toxicological and prognostic concordance of pre-neoplastic and neoplastic lesions arising in either species. This analysis serves as a rigorous demonstration of the framework's utility in increasing transparency and consistency in evidence-based assessment of MOA hypotheses in toxicological models and determining relevance to human health.

Elongated particulate burden in an individual who died of mesothelioma and had an occupational history as a talc "mucker".

INTRODUCTION: Tissue from a 77-year-old man diagnosed with mesothelioma was referred with a request for identification of the presence of fibrous structures in tissue samples. The individual's work history including working as a "mucker" at a specific "industrial" talc mine. METHODS: Ferruginous bodies in the tissue digests as well as asbestos fibers were found. A bulk sample of a talc containing product from that mine was also analyzed. DISCUSSIONS/CONCLUSIONS: The correlation between the unique asbestos mineral/fibrous content of the talc to which he was exposed and findings of the same type of asbestos found in his lung is discussed. The type of asbestos found (tremolite) is a "non-commercial" type of asbestos that has been identified in some talc deposits. Tremolite, like all forms of asbestos is a causative agent for mesothelioma-the disease from which this individual suffered.

Hexavalent chromium exposure activates the non-canonical nuclear factor kappa B pathway to promote immune checkpoint protein programmed death-ligand 1 expression and lung carcinogenesis.

Lung cancer is the leading cause of cancer-related death worldwide; however, the mechanism of lung carcinogenesis has not been clearly defined. Chronic exposure to hexavalent chromium [Cr(VI)], a common environmental and occupational pollutant, causes lung cancer, representing an important lung cancer etiology factor. The mechanism of how chronic Cr(VI) exposure causes lung cancer remains largely unknown. By using cell culture and mouse models and bioinformatics analyses of human lung cancer gene expression profiles, this study investigated the mechanism of Cr(VI)-induced lung carcinogenesis. A new mouse model of Cr(VI)-induced lung carcinogenesis was developed as evidenced by the findings showing that a 16-week Cr(VI) exposure (CaCrO4, 100 µg per mouse once per week) via oropharyngeal aspiration induced lung adenocarcinomas in male and female A/J mice, whereas none of the sham-exposed control mice had lung tumors. Mechanistic studies revealed that chronic Cr(VI) exposure activated the non-canonical NFκB pathway through the long non-coding RNA (lncRNA) ABHD11-AS1/deubiquitinase USP15-mediated tumor necrosis factor receptor-associated factor 3 (TRAF3) down-regulation. The non-canonical NFκB pathway activation increased the interleukin 6 (IL-6)/Janus kinase (Jak)/signal transducer and activator of transcription 3 (Stat3) signaling. The activation of the IL-6/Jak signaling axis by Cr(VI) exposure not only promoted inflammation but also stabilized the immune checkpoint molecule programmed death-ligand 1 (PD-L1) protein in the lungs, reducing T lymphocyte infiltration to the lungs. Given the well-recognized critical role of PD-L1 in inhibiting anti-tumor immunity, these findings suggested that the lncRNA ABHD11-AS1-mediated non-canonical NFκB pathway activation and PD-L1 up-regulation may play important roles in Cr(VI)-induced lung carcinogenesis.

A ketogenic diet rich in fish oil is superior to other fats in preventing NNK-induced lung cancer in A/J mice.

Given that ketogenic diets (KDs) are extremely high in dietary fat, we compared different fats in KDs to determine which was the best for cancer prevention. Specifically, we compared a Western and a 15% carbohydrate diet to seven different KDs, containing either Western fats or fats enriched in medium chain fatty acids (MCTs), milk fat (MF), palm oil (PO), olive oil (OO), corn oil (CO) or fish oil (FO) for their ability to reduce nicotine-derived nitrosamine ketone (NNK)-induced lung cancer in mice. While all the KDs tested were more effective at reducing lung nodules than the Western or 15% carbohydrate diet, the FO-KD was most effective at reducing lung nodules. Correlating with this, mice on the FO-KD had low blood glucose and the highest ß-hydroxybutyrate level, lowest liver fatty acid synthase/carnitine palmitoyl-1a ratio and a dramatic increase in fecal Akkermansia. We found no liver damage induced by the FO-KD, while the ratio of total cholesterol/HDL was unchanged on the different diets. We conclude that a FO-KD is superior to KDs enriched in other fats in reducing NNK-induced lung cancer, perhaps by being the most effective at skewing whole-body metabolism from a dependence on glucose to fats as an energy source.

Circ0087385 promotes DNA damage in benzo(a)pyrene-induced lung cancer development by upregulating CYP1A1.

Increasing environmental genotoxic chemicals have been shown to induce epigenetic alterations. However, the interaction between genetics and epigenetics in chemical carcinogenesis is still not fully understood. Here, we constructed an in vitro human lung carcinogenesis model (16HBE-T) by treating human bronchial epithelial cells with a typical significant carcinogen benzo(a)pyrene (BaP). We identified a novel circular RNA, circ0087385, which was overexpressed in 16HBE-T and human lung cancer cell lines, as well as in lung cancer tissues and serum exosomes from lung cancer patients. The upregulated circ0087385 after exposure to BaP promoted DNA damage in the early stage of chemical carcinogenesis and affected the cell cycle, proliferation, and apoptosis of the malignantly transformed cells. Overexpression of circ0087385 enhanced the expression of cytochrome P450 1A1 (CYP1A1), which is crucial for metabolically activating BaP. Interfering with circ0087385 or CYP1A1 reduced the levels of ultimate carcinogen benzo(a)pyrene diol epoxide (BPDE) and BPDE-DNA adducts. Interfering with CYP1A1 partially reversed the DNA damage induced by high expression of circ0087385, as well as decreased the level of BPDE and BPDE-DNA adducts. These findings provide novel insights into the interaction between epigenetics and genetics in chemical carcinogenesis which are crucial for understanding the epigenetic and genetic toxicity of chemicals.