MiR-218-5p/EGFR Signaling in Arsenic-Induced Carcinogenesis.

BACKGROUND: Arsenic is a well-known carcinogen inducing lung, skin, bladder, and liver cancer. Abnormal epidermal growth factor receptor (EGFR) expression is common in lung cancer; it is involved in cancer initiation, development, metastasis, and treatment resistance. However, the underlying mechanism for arsenic-inducing EGFR upregulation remains unclear. METHODS: RT-PCR and immunoblotting assays were used to detect the levels of miR-218-5p and EGFR expression. The Luciferase assay was used to test the transcriptional activity of EGFR mediated by miR-218-5p. Cell proliferation, colony formation, wound healing, migration assays, tube formation assays, and tumor growth assays were used to study the function of miR-218-5p/EGFR signaling. RESULTS: EGFR and miR-218-5p were dramatically upregulated and downregulated in arsenic-induced transformed (As-T) cells, respectively. MiR-218-5p acted as a tumor suppressor to inhibit cell proliferation, migration, colony formation, tube formation, tumor growth, and angiogenesis. Furthermore, miR-218-5p directly targeted EGFR by binding to its 3'-untranslated region (UTR). Finally, miR-218-5p exerted its antitumor effect by inhibiting its direct target, EGFR. CONCLUSION: Our study highlights the vital role of the miR-218-5p/EGFR signaling pathway in arsenic-induced carcinogenesis and angiogenesis, which may be helpful for the treatment of lung cancer induced by chronic arsenic exposure in the future.

Epigenetic Regulation in Chromium-, Nickel- and Cadmium-Induced Carcinogenesis.

Environmental and occupational exposure to heavy metals, such as hexavalent chromium, nickel, and cadmium, are major health concerns worldwide. Some heavy metals are well-documented human carcinogens. Multiple mechanisms, including DNA damage, dysregulated gene expression, and aberrant cancer-related signaling, have been shown to contribute to metal-induced carcinogenesis. However, the molecular mechanisms accounting for heavy metal-induced carcinogenesis and angiogenesis are still not fully understood. In recent years, an increasing number of studies have indicated that in addition to genotoxicity and genetic mutations, epigenetic mechanisms play critical roles in metal-induced cancers. Epigenetics refers to the reversible modification of genomes without changing DNA sequences; epigenetic modifications generally involve DNA methylation, histone modification, chromatin remodeling, and non-coding RNAs. Epigenetic regulation is essential for maintaining normal gene expression patterns; the disruption of epigenetic modifications may lead to altered cellular function and even malignant transformation. Therefore, aberrant epigenetic modifications are widely involved in metal-induced cancer formation, development, and angiogenesis. Notably, the role of epigenetic mechanisms in heavy metal-induced carcinogenesis and angiogenesis remains largely unknown, and further studies are urgently required. In this review, we highlight the current advances in understanding the roles of epigenetic mechanisms in heavy metal-induced carcinogenesis, cancer progression, and angiogenesis.

Epigenetic Dysregulations in Arsenic-Induced Carcinogenesis.

Arsenic is a crucial environmental metalloid whose high toxicity levels negatively impact human health. It poses significant health concerns to millions of people in developed and developing countries such as the USA, Canada, Bangladesh, India, China, and Mexico by enhancing sensitivity to various types of diseases, including cancers. However, how arsenic causes changes in gene expression that results in heinous conditions remains elusive. One of the proposed essential mechanisms that still has seen limited research with regard to causing disease upon arsenic exposure is the dysregulation of epigenetic components. In this review, we have extensively summarized current discoveries in arsenic-induced epigenetic modifications in carcinogenesis and angiogenesis. Importantly, we highlight the possible mechanisms underlying epigenetic reprogramming through arsenic exposure that cause changes in cell signaling and dysfunctions of different epigenetic elements.

Neuroendocrine modulation of predator avoidance/prey capture tradeoffs: Role of tectal NPY2R receptors.

The optic tectum rapidly inhibits food intake when a visual threat is present. Anatomical and electrophysiological evidence support a role for neuropeptide Y (NPY), originating from cells in the thalamus, in the tectal inhibition of prey capture. Here we test the hypothesis that tectal NPY receptor type 2 (NPY2R) influences prey-capture and predator-avoidance responses in the African clawed frog, Xenopus laevis. We tested two questions: 1) Does tectal NPY administration decrease food intake and alter prey-capture behavior? 2) Does tectal administration of a NPY2R antagonist increase food intake, alter prey-capture behavior, and alter predator avoidance behavior? NPY microinjected bilaterally into the tecta failed to significantly alter food intake at any dose tested, although predator presence significantly reduced food intake. However, NPY differentially altered discrete components of prey capture including increasing the latency to contact food and reducing the amount of time in contact with food. These effects were blocked by the NPY2R antagonist BIIE0246. Additionally, BIIE0246 elevated food intake on its own after bilateral tectal microinjection. Furthermore, BIIE0246 reversed the reduction of food intake caused by exposure to a predator. Overall, these findings indicate that tectal NPY2R activation causes frogs to consume food more quickly, which may be adaptive in predator-rich environments. Blocking tectal NPY2R increases baseline food intake and reduces or eliminates predator-induced changes in prey capture and food intake.