Chronic cadmium exposure aggravates malignant phenotypes of nasopharyngeal carcinoma by activating the Wnt/β-catenin signaling pathway via hypermethylation of the casein kinase 1α promoter

Abstract

BackgroundOur previous study has shown that cadmium (Cd) exposure is not only a risk factor for nasopharyngeal carcinoma (NPC), but also correlated with the clinical stage and lymph node metastasis. However, the underlying molecular events of Cd involved in NPC progression remain to be elucidated.PurposeThe objective of this study was to decipher how Cd impacts the malignant phenotypes of NPC cells.MethodsNPC cell lines CNE-1 and CNE-2 were continuously exposed with 1 μM Cd chloride for 10 weeks, designating as chronic Cd treated NPC cells (CCT-NPC). MTT assay, colony formation assay and xenograft tumor growth were used to assess cell viability in vitro and in vivo. Transwell assays were performed to detect cell invasion and migration. The protein levels of E-cadherin, N-cadherin, Vimentin as well as β-catenin and casein kinase 1α(CK1α) were measured by Western blot. Immunofluorescence staining was used to observe the distribution of filament actin (F-actin), β-catenin and CK1α. The mRNA levels of downstream target genes of β-catenin were detected by RT-PCR. Wnt/β-catenin signaling activity was assessed by TOPFlash/FOPFlash dual luciferase report system. MS-PCR was used to detect the methylation status of CK1α. Finally, the activation of Wnt/β-catenin pathway and cell biological properties were examined following treatment of CCT-NPC cells with 5-aza-2-deoxy-cytidine(5-aza-CdR).ResultsCCT-NPC cells showed an increase in cell proliferation, colony formation, invasion and migration compared to the parental cells. Cd also induced cytoskeleton reorganization and epithelial-to-mesenchymal transition. Upregulation and nuclear translocation of β-catenin and increased luciferase activity accompanied with transcription of downstream target genes were found in CCT-NPC cells. Treatment of CCT-CNE1 cells with 5-aza-CdR could reverse the hypermethylation of CK1α and attenuate the cell malignancy.ConclusionThese results support a role for chronic Cd exposure as a driving force for the malignant progression of NPC via epigenetic activation of the Wnt/β-catenin pathway.

Glucose and lipid lowering effects of Enhydra fluctuans extract in cadmium treated normal and type-2 diabetic model rats

“…Therefore, Cd can easily enter into the food chain or efficiently transfer to plants [9]. This toxic heavy metal has many adverse health effects [10] and studies have suggested that Cd induced different types of cancers [11, 12], liver- and renal dysfunction [13], diabetes and cardiovascular diseases [14]. In diabetes, it exacerbates beta cell dysfunction and studies showed varied results [15–17].…”

Wnt pathway: A mechanism worth considering in endocrine disrupting chemical action

“…Wnt/β-catenin pathway has also been investigated in nasopharyngeal carcinoma cell lines exposed to cadmium. In this study chronic low-dose Cadmium enhanced malignant progression, including more proliferative and aggressive characteristics through the activation of the Wnt/β-catenin pathway and DNA methylation (Peng et al, 2019).…”

Endocrine pancreas in rats chronically treated with Cadmium

“…Izloženost kadmijumu je povezana sa karcinomom nasofaringsa, pluća, pankreasa,jetre, bubrega, dojke, prostate i mokraćne bešike u ljudi 9,10,11 . Zbog toga su Internacionalna Agencija za Istraživanje Kancera (International Agency for Research on Cancer) i Nacionalni Toksikološki Program SAD (National Toxicology Program of the USA) svrstali kadmijum u grupu humanih karcinogena I kategorije 11,12 .…”

“…U ljudi kadmijum najčešće ulazi u organizam inhalacijom,preko digestivnog trakta i preko kože.Kada dospe u cirkulaciju kadmijum se transportuje do depoa, Ranije se smatralo da se oko 50% kadmijuma akumulira samo u jetri, bubrezima ili mišićima, međutim ispitivanja koncentracija kadmijuma u štitastoj žlezdi u bolesnika obolelih od "itai itai" su pokazala da se tkivna koncentracija kadmijuma u tireoideji, kod muškaraca, nalazi na drugom mestu, iza koncentracija kadmijuma u jetri, a kod žena na trećem mestu, iza jetre i pankreasa 13 . Kadmijum se eliminiše iz organizma urinom i preko digestivnog trakta, ali zbog prekomerne akumulacije u krvi i u depoima i male ekskrecije on ima biološki poluživot čak od 15-40 godina 9 . Procenjeno je da više od 80% kadmijuma koji se unese hranom dolazi od cerealija, povrća i paradajiza 14 .…”