Simple Summary Previous clinical studies have suggested a relationship between obstructive sleep apnea and some types of cancer. This relationship is very heterogeneous, however. This heterogeneity probably depends on the complex pathophysiological pathways activated. It seems that the hypoxia inducible transcription factor, a molecule expressed in situations of hypoxemia such as obstructive sleep apnea, is a key factor. In recent years, however, some new pathophysiological pathways have been shown to be involved, including a large number of biomarkers, pathways related to immune cell dysfunction, exosomes, genetics, and even microbiome alterations. Furthermore, there is an array of tumor cell lines, each with a different capacity to respond to intermittent hypoxia. Both clinical and murine model studies suggest that tumors, such as melanoma and some histological types of breast and lung cancer, could respond in different ways from cancer cell lines in the prostate or the liver. Abstract Several epidemiological and clinical studies have suggested a relationship between obstructive sleep apnea (OSA) and a higher incidence or severity of cancer. This relationship appears to be dependent on a myriad of factors. These include non-modifiable factors, such as age and gender; and modifiable or preventable factors, such as specific comorbidities (especially obesity), the use of particular treatments, and, above all, the histological type or location of the cancer. Heterogeneity in the relationship between OSA and cancer is also related to the influences of intermittent hypoxemia (a hallmark feature of OSA), among others, on metabolism and the microenvironment of different types of tumoral cells. The hypoxia inducible transcription factor (HIF-1α), a molecule activated and expressed in situations of hypoxemia, seems to be key to enabling a variety of pathophysiological mechanisms that are becoming increasingly better recognized. These mechanisms appear to be operationally involved via alterations in different cellular functions (mainly involving the immune system) and molecular functions, and by inducing modifications in the microbiome. This, in turn, may individually or collectively increase the risk of cancer, which is then, further modulated by the genetic susceptibility of the individual. Here, we provide an updated and brief review of the different pathophysiological pathways that have been identified and could explain the relationship between OSA and cancer. We also identify future challenges that need to be overcome in this intriguing field of research.

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Potential Pathophysiological Pathways in the Complex Relationships between OSA and Cancer

Applying multi‐omics toward tumor microbiome research

Colorectal cancer (CRC) is one of the most common malignant tumor types occurring in the digestive system. The incidence of CRC has exhibits yearly increases and the mortality rate among patients with CRC is high. The Wnt/β-catenin signaling pathway, which is associated with carcinogenesis, is abnormally activated in CRC. Most patients with CRC have adenomatous polyposis coli mutations, while half of the remaining patients have β-catenin gene mutations. Therefore, targeting the Wnt/β-catenin signaling pathway for the treatment of CRC is of clinical value. In recent years, with in-depth research on the Wnt/β-catenin signaling pathway, inhibitors have been developed that are able to suppress or hinder the development and progression of CRC. In the present review, the role of the Wnt/β-catenin signaling pathway in CRC is summarized, the research status on Wnt/β-catenin pathway inhibitors is outlined and potential targets for inhibition of this pathway are presented.

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Blocking the Wnt/β-catenin signaling pathway to treat colorectal cancer: Strategies to improve current therapies (Review)

This article study the influences of fermented wheat germ on rats in terms of the blood glucose, insulin level, serum lipid level, cholesterol metabolism, triglyceride metabolism and enzyme activity on the basis of the high-fat rat model. High fat rats were fed for modeling, and then the serum and liver were collected after sacrifice. Total cholesterol (TC), triglyceride (TG), total superoxide dismutase (SOD), Superoxide dismutase (T-SOD), glutathione peroxidase (GSH-PX), Malonic dialdehyde (MDA), lecithin cholesterol acyltransferase (lecithin cholesterol), Acyltransferase (LCAT), LDL-C, blood glucose and insulin were measured. Fermented wheat germ can significantly increase the levels of insulin and blood glucose in high-fat rats. Fermented wheat germ for 60 days did not affect the levels of serum LDL-C and TG in high-fat rats, but could significantly reduce the level of serum TC. Fermented wheat germ for 60 days did not affect the activities of serum GSH-Px, T-SOD, LCAT and T-SOD, MDA and total lipase in high-fat rats, but it could significantly reduce the activity of serum MDA and increase the activity of GSH-PX in liver. Fermented wheat germ could reduce the protein expression of CYP7A1, induced p-AMPK protein expression, but had no effect on HMGR. Fermented wheat germ can significantly reduce the level of serum cholesterol in high-fat model rats by AMPK signaling pathway, and affect some cholesterol metabolism and triglyceride metabolism related enzyme activities to a certain extent. 

Regulatory mechanism of fermented wheat germ on lipid metabolism in hyperlipidemia rats via activation of AMPK pathway

Forkhead box M1 (FOXM1), a vital member of the Forkhead box family of transcription factors, helps in mediating oncogenesis. However, limited knowledge exists regarding the mechanistic insights into the FOXM1 gene regulation. p68, an archetypal member of the DEAD-box family of RNA helicases, shows multifaceted action in cancer progression by arbitrating RNA metabolism and transcriptionally coactivating transcription factors. Here, we report a novel mechanism of alliance between p68 and the Wnt/β-catenin pathway in regulating FOXM1 gene expression and driving colon carcinogenesis. Initial bioinformatic analyses highlighted elevated expression levels of FOXM1 and p68 in colorectal cancer datasets. Immunohistochemical assays confirmed that FOXM1 showed a positive correlation with p68 and β-catenin in both normal and colon carcinoma patient samples. Overexpression of p68 and β-catenin increased the protein and mRNA expression profiles of FOXM1, and the converse correlation occurred during downregulation. Mechanistically, overexpression and knockdown of p68 and β-catenin elevated and diminished FOXM1 promoter activity respectively. Additionally, Chromatin immunoprecipitation assay demonstrated the occupancy of p68 and β-catenin at the TCF4/LEF binding element (TBE) sites on the FOXM1 promoter. Thiostrepton delineated the effect of FOXM1 inhibition on cell proliferation and migration. Colony formation assay, migration assay, and cell cycle data reveal the importance of the p68/β-catenin/FOXM1 axis in oncogenesis. Collectively, our study mechanistically highlights the regulation of FOXM1 gene expression by p68 and β-catenin in colorectal cancer.

https://www.biorxiv.org/content/biorxiv/early/2022/10/28/2022.10.28.514256.full.pdf

The DEAD-box protein p68 and β-catenin: the crucial regulators of FOXM1 gene expression in arbitrating colorectal cancer

As one of the most common malignancies worldwide, gastric cancer contributes to cancer death with a high mortality rate partly responsible for its out-of-control progression as well as limited diagnosis. DNA methylation, one of the epigenetic events, plays an essential role in the carcinogenesis of many cancers, including gastric cancer. Long non-coding RNAs have emerged as the significant factors in the cancer progression functioned as the oncogene genes, the suppressor genes and regulators of signaling pathways over the decade. Intriguingly, increasing reports, recently, have claimed that abnormal DNA methylation regulates the expression of lncRNAs as tumor suppressor genes in gastric cancer and lncRNAs as regulators could exert the critical influence on tumor progression through acting on DNA methylation of other cancer-related genes. In this review, we summarized the DNA methylation-associated lncRNAs in gastric cancer which play a large impact on tumor progression, such as proliferation, invasion, metastasis and so on. Furthermore, the underlying molecular mechanism and signaling pathway might be developed as key points of gastric cancer range from diagnosis to prognosis and treatment in the future. 

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Regulatory function of DNA methylation mediated lncRNAs in gastric cancer

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Hyperlipidemia refers to a chronic disease caused by systemic metabolic disorder, and its pathophysiology is very complex. Shanmei capsule (SM) is a famous preparation with a long tradition of use for anti-hyperlipidemia treatment in China. However, the regulation mechanism of SM on hyperlipidemia has not been elucidated so far. In this study, a combination of UPLC-Q-TOF/MS techniques and 16S rDNA gene sequencing was performed to investigate the effects of SM treatment on plasma metabolism-mediated change and intestinal homeostasis. The results indicated that SM potently ameliorated high-fat diet-induced glucose and lipid metabolic disorders and reduced the histopathological injury. Pathway analysis indicated that alterations of differential metabolites were mainly involved in glycerophospholipid metabolism, linolenic acid metabolism, α-linoleic acid metabolism, and arachidonic acid metabolism. These changes were accompanied by a significant perturbation of intestinal microbiota characterized by marked increased microbial richness and changed microbiota composition. There were many genera illustrating strong correlations with hyperlipidemia-related markers (e.g., weight gains, GLU, and total cholesterol), including the Lachnospiraceae NK4A136 group and the Lachnospiraceae NK4B4 group. Overall, this study initially confirmed that hyperlipidemia is associated with metabolic disturbance and intestinal microbiota disorders, and SM can be employed to help decrease hyperlipidemia risk, including improving the abnormal metabolic profile and maintaining the gut microbial environment.

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Metabolomic and Microbial Remodeling by Shanmei Capsule Improves Hyperlipidemia in High Fat Food-Induced Mice

Colorectal cancer (CRC) ranks third in terms of global incidence and second in terms of death toll among malignant tumors. Gut microbiota are involved in the formation, development, and responses to different treatments of CRC. Under normal physiological conditions, intestinal microorganisms protect the intestinal mucosa, resist pathogen invasion, and regulate the proliferation of intestinal mucosal cells via a barrier effect and inhibition of DNA damage. The composition of gut microbiota and the influences of diet, drugs, and gender on the composition of the intestinal flora are important factors in the early detection of CRC and prediction of the results of CRC treatment. Regulation of gut microbiota is one of the most promising new strategies for CRC treatment, and it is essential to clarify the effect of gut microbiota on CRC and its possible mechanisms to facilitate the prevention and treatment of CRC. This review discusses the role of gut microbiota in the pathogenesis of CRC, the potential of gut microbiota as biomarkers for CRC, and therapeutic approaches to CRC based on the regulation of gut microbiota. It might provide new ideas for the use of gut microbiota in the prevention and treatment of CRC in the near future and thus reduce the incidence of CRC.

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Therapeutic approaches to colorectal cancer via strategies based on modulation of gut microbiota

On a global scale, the incidence and mortality rates of lung cancer are gradually increasing year by year. A number of bad habits and environmental factors are associated with lung cancer, including smoking, second-hand smoke exposure, occupational exposure, respiratory diseases and genetics. At present, low-dose spiral computed tomography is routinely the first choice in the diagnosis of lung cancer. However, pathological examination is still the gold standard for the diagnosis of lung cancer. Based on the classification and stage of the cancer, treatment options such as surgery, radiotherapy, chemotherapy, targeted therapy and immunotherapy are available. The activation of the EGFR pathway can promote the survival and proliferation of tumor cells, and the VEGF pathway can promote the formation of blood vessels, thereby promoting tumor growth. In non-small cell lung cancer (NSCLC) with EGFR mutation, EGFR activation can promote tumor growth by promoting VEGF upregulation through a hypoxia-independent mechanism. The upregulation of VEGF can make tumor cells resistant to EGFR inhibitors. In addition, the expression of the VEGF signal is also affected by other factors. Therefore, the use of a single EGFR inhibitor cannot completely inhibit the expression of the VEGF signal. In order to overcome this problem, the combination of VEGF inhibitors and EGFR inhibitors has become the method of choice. Dual inhibition can not only overcome the resistance of tumor cells to EGFR inhibitors, but also significantly increase the progression-free survival time of patients with NSCLC. The present review discusses the associations between the EGFR and VEGF pathways, and the characteristics of dual inhibition of the EGFR-VEGF pathway.

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Qian Wang

Papers

Regulatory function of DNA methylation mediated lncRNAs in gastric cancer

Regulatory function of DNA methylation mediated lncRNAs in gastric cancer

Metabolomic and Microbial Remodeling by Shanmei Capsule Improves Hyperlipidemia in High Fat Food-Induced Mice

Therapeutic approaches to colorectal cancer via strategies based on modulation of gut microbiota

Dual inhibition of EGFR-VEGF: An effective approach to the treatment of advanced non-small cell lung cancer with EGFR mutation (Review)