Autophagy and oxidative stress, which are closely related, play important roles in cellular stress response, defense function, and damage. Arsenic is one of the chemical pollutant, which is widely distributed in natural environment. International agency for research on cancer (IARC) has made it clear that arsenic and its compounds are carcinogens. However, the mechanism of carcinogenesis induced by arsenic still remains obscure. Recently, researchers have found that autophagy and oxidative stress play an important role in the process of arsenic carcinogenesis. In this paper, we have reviewed the types and regulation of cellular autophagy, the roles of autophagy and oxidative stress in tumorigenesis, and the effects of arsenic on carcinogenesis.

The glucose metabolism pathways including glycolysis and oxidative phosphorylation in vivo.The metabolism of tumor cells depends on glycolysis,which enhances the adaptability of tumor cells to the microenvironment and promotes the proliferation of tumor cells,which is called Warburg effect.Arsenic is one of the chemical pollutants,which is widely distributed in natural environment.International agency for research on cancer (IARC) has made it clear that arsenic and its compounds are carcinogens.However,the mechanism of carcinogenesis induced by arsenic still remains obscure.Recently,researchers have found that Warburg effect plays an important role in the process of arsenic carcinogenesis.In this paper,we have reviewed the definition and function of glycolysis,its relationship with inflammation and tumorigenesis,and the role of Warburg effect in arsenic carcinogenesis.

Objective To investigate the role of exosomal microRNA(miR)-191 derived from NaAsO2-transformed cells in proliferation of human liver L-02 cells.Methods The normal wild-type L-02 cells (recipient L-02 cells)were treated with media or exosome derived from 2 μmol/L NaAsO2-transformed L-02 cells.Anti-miR-191 and anti-miR-NC were transfected into NaAsO2-transformed L-02 (T-L-02) cells by lipofectamineTM 2000,respectively,while untreated group was set as control.The expression of miR-191 was detected by qRT-PCR.Cell proliferation was evaluated by CCK-8 assay.Results The proliferation [(207 ± 24)％ vs (105 ± 21)％,t =5.462,P ＜ 0.01] and the expression of miR-191 [(206 ± 25)％ vs (105 ± 20)％,t =4.116,P ＜ 0.05] of recipient L-02 cells were significantly increased in the transformed L-02 cells media (T-CM) treated group compared with in the normal L-02 cells media (CM) group.Several concentrations of exosomes derived from CM did not change the proliferation and miR-191 expression of recipient L-02 cells (F =2.213,2.213,all P ＞ 0.05).Several concentrations of exosomes derived from T-CM increased the proliferation and miR-191 expression of recipient L-02 cells in a dose-response manner (F =10.910,4.553,P ＜ 0.01 or ＜ 0.05).The proliferation [(160 ± 32)％ vs (102 ± 8)％,(203 ± 7)％ vs (111 ± 5)％,t =2.999,18.750,P ＜ 0.05 or ＜ 0.01] of recipient L-02 cells treated with 20 or 50 mg/L exosomes derived from T-CM was higher than that treated with the same concentration of exosomes derived from CM.The expression of miR-191 [(166 ± 13)％ vs (113 ±9)％,(211 ± 55)％ vs (102 ± 8)％,(206 ± 31)％ vs (105 ± 6)％,t =5.611,3.357,5.509,P ＜ 0.05 or ＜ 0.01] of recipient L-02 cells treated with 10,20 or 50 mg/L exosomes derived from T-CM was higher than that treated with the same concentration of exosomes derived from CM.The miR-191 levels of T-L-02 cells [(39 ± 10)％ vs (100 ± 0)％ or (106 ±17)％,all P ＜ 0.01] or exosomes [(30 ± 19)％ vs (100 ± 0)％ or (104 ± 17)％,all P ＜ 0.01] in the anti-miR-191 treated group were significantly lower than that in the untreated group or anti-miR-NC treated group.The exosomes derived from untreated group promoted the proliferation [(395 ± 31)％ vs (100 ± 0)％,t =16.290,P ＜ 0.01] and miR-191 expression [(208 ± 47)％ vs (100 ± 0)％,t =4.015,P ＜ 0.05] of recipient L-02 cells.The proliferation [(157 ± 19)％ vs (395 ± 31)％ or (411 ± 55)％,P ＜ 0.05] and miR-191 expression of [(103 ± 44)％ vs (208 ± 47)％ or (197 ± 37)％,P＜ 0.05 or ＜ 0.01] of recipient L-02 cells treated with exosomes derived from anti-miR-191 treated group were lower than those treated with exosomes derived from untreated group or anti-miR-NC treated group.Conclusion The exosomal miR-191 secreted by NaAsO2-transformed L-02 cells promotes proliferation of normal human L-02 cells.

Objective: To investigate the role of hypoxia-inducible factor-1α (HIF-1α) in arsenite-induced epithelial-mesenchymal transition (EMT) and malignant transformation of human liver epithelial cells (L-02 cells). Methods: After the L-02 cells were chronic treated with 2.0 μmol/L NaAsO₂ for 0 (reference), 10, 20, or 30 passages, con siRNA or HIF-1α siRNA was transfected into arsenite-transformed L-02 (T-L-02) cells by lipofectamine^TM2000 and were set as T-L-02+con siRNA group and T-L-02+HIF-1α siRNA group as well as L-02 group and T-L-02 group, EMT index and levels of HIF-1α were detected by western blots. The reporter assays were performed to determine if HIF-1α directly regulate Snail transcriptional activity, and soft agar colony formation and Transwell assay were used to detect the malignancy, invasion, and migration ability of cells. Results: When L-02 cells were treated for 10 generations with 2 μmol/L NaAsO₂, relative expressions of E-cadherin were gradually increased compared to control cells, while the levels of N-cadherin, Snail, and HIF-1α were gradually increased in the L-02 cells compared to control cells, showing the longer the treatment time was, the more obvious the change was (P<0.05) . Down regulating the level of HIF-1α by siNRA caused E-cadherin levels to rise compared to T-L-02 group, while the levels of N-cadherin and Snail fall back compared to T-L-02 group (P<0.05) . Double luciferase reporter gene assays showed that HIF-1α directly targeted Snail to regulate its expression. Soft agar colony formation and Transwell assays showed that the numbers of formed colonies, invasion cells, and metastasis cells of cells in T-L-02 group were all lower than those in L-02 group (P<0.05) . Conclusion HIF-1α is involved in arsenite-induced EMT and malignant transformation of human liver epithelial cells via regulating Snail.