Chronic Arsenic Exposure and Angiogenesis in Human Bronchial Epithelial Cells via the ROS/miR-199a-5p/HIF-1 α /COX-2 Pathway

Abstract

Background: Environmental and occupational exposure to arsenic is a major public health concern. Although it has been identified as a human carcinogen, the molecular mechanism underlying the arsenic-induced carcinogenesis is not well understood.Objectives: We aimed to determine the role and mechanisms of miRNAs in arsenic-induced tumor angiogenesis and tumor growth.Methods: We utilized an in vitro model in which human lung epithelial BEAS-2B cells were transformed through long-term exposure to arsenic. A human xenograft tumor model was established to assess tumor angiogenesis and tumor growth in vivo. Tube formation assay and chorioallantoic membranes assay were used to assess tumor angiogenesis.Results: We found that miR-199a-5p expression levels were more than 100-fold lower in arsenic-transformed cells than parental cells. Re-expression of miR-199a-5p impaired arsenic-induced angiogenesis and tumor growth through its direct targets HIF-1α and COX-2. We further showed that arsenic induced COX-2 expression through HIF-1 regulation at the transcriptional level. In addition, we demonstrated that reactive oxygen species are an upstream event of miR-199a-5p/ HIF-1α/COX-2 pathway in arsenic-induced carcinogenesis.Conclusion: The findings establish critical roles of miR-199a-5p and its downstream targets HIF-1/COX-2 in arsenic-induced tumor growth and angiogenesis.Citation: He J, Wang M, Jiang Y, Chen Q, Xu S, Xu Q, Jiang BH, Liu LZ. 2014. Chronic arsenic exposure and angiogenesis in human bronchial epithelial cells via the ROS/miR-199a-5p/HIF-1α/COX-2 Pathway. Environ Health Perspect 122:255–261; http://dx.doi.org/10.1289/ehp.1307545

Effects of 17β-estradiol and 2-methoxyestradiol on the oxidative stress-hypoxia inducible factor-1 pathway in hypoxic pulmonary hypertensive rats

“…A previous study demonstrated that factors other than hypoxia may enhance HIF-1α mRNA expression, as the HIF-1 level did not increase in direct correlation to oxygen concentration (22). Accumulating evidence suggests that oxidative stress is involved in the regulation of HIF-1 expression and activity (23)(24)(25)(26)(27).…”

“…Previous research demonstrated that augmenting SOD2-increased hydrogen peroxide-mediated redox signaling inhibited HIF-1α activity and reduced pulmonary artery smooth muscle cell proliferation (24). Recent studies have reported that oxidative stress regulates the expression of HIF-1α at both the protein and mRNA levels (25)(26)(27). A study on arsenic-induced carcinogenesis demonstrated that arsenic-induced ROS increases HIF-1α transcription via inhibition of miR-199a expression (25).…”

“…Recent studies have reported that oxidative stress regulates the expression of HIF-1α at both the protein and mRNA levels (25)(26)(27). A study on arsenic-induced carcinogenesis demonstrated that arsenic-induced ROS increases HIF-1α transcription via inhibition of miR-199a expression (25). Sasabe et al (26) revealed that intracellular ROS, produced following the knockdown of Mn-SOD, enhanced HIF-1α expression in oral squamous cell carcinoma cells through transcriptional, translational and posttranslational regulation under normoxic and hypoxic conditions.…”

Oxidative DNA damage enhances the carcinogenic potential of in vitro chronic arsenic exposures

“…Back to the case of inorganic arsenic, recent works described that exposure of lung epithelial cells to arsenite retrieved increased proliferation rates and gain of anchorage-independent cell growth that were reverted by inhibiting ROS production with catalase (Carpenter et al 2011). In the same lung target cells, other authors showed that ROS modulate arsenic-induced tumor growth and angiogenesis by downregulating several miRNAs in control of such transformation features (He et al 2014). With respect to epidemiological studies, it has been described that 8-OH-dG lesions occurred at a higher frequency in arsenic-related skin neoplasms (Matsui et al 1999) and in lymphocytes from arsenic-exposed individuals (Basu et al 2005).…”

Combination of celecoxib and PD184161 exerts synergistic inhibitory effects on gallbladder cancer cell proliferation

“…Under physiological conditions, COX-2 protein expression is weak or absent in the majority of normal tissues (25); by contrast, under pathological situations, such as in tumors or inflammation, its expression may be induced by a variety of inflammatory cytokines, which are produced by tumors or their microenvironment. It has been documented that interleukin (IL)-1 (26), IL-8 (27), nuclear factor κB (28) and hypoxia inducible factor 1α (29) can stimulate the expression of COX-2. Most of these factors are abundant in GBC tissues, which may be the reason for the aberrant activation of COX-2 and p-ERK1/2 in GBC tissues and cell lines.…”