Anoikis resistance is an essential prerequisite for tumor metastasis, but the underlying molecular mechanisms remain unknown. Herein, we report that the oncoprotein hepatitis B X-interacting protein (HBXIP) is prominently upregulated in breast cancer cells following ECM detachment. Altering HBXIP expression can impair the anchorage-independent growth ability of tumor cells. Mechanistically, HBXIP, which binds to Kelch-like ECH-associated protein 1 (Keap1) to activate nuclear factor E2-related factor 2 (Nrf2), contains a cis-acting antioxidant response element (ARE) in the gene promoter and is a target gene of Nrf2. The HBXIP/Nrf2 axis forms a reciprocal positive feedback loop that reinforces the expression and tumor-promoting actions of each protein. In response to ECM detachment, Nrf2 reduces reactive oxygen species (ROS) accumulation, protects the mitochondrial membrane potential and increases cellular ATP, GSH and NADPH levels to maintain breast cancer cell survival. Meanwhile, the reinforcement of HBXIP induced by Nrf2 inhibits JNK1 activation by inhibiting ubiquitin-mediated degradation of Prdx1, which also plays an essential role in promoting ECM-detached cell survival. Furthermore, a strong positive correlation was identified between HBXIP expression and Prdx1 expression in clinical breast cancer tissues and TCGA Pan-Cancer Atlas clinical data of breast invasive carcinoma based on the cBioPortal cancer genomics database. Co-expression of HBXIP and Prdx1 predicts a poor prognosis for breast cancer patients. Collectively, our findings reveal a significant mechanism by which the HBXIP/Nrf2 feedback loop contributes to anoikis resistance by maintaining redox homeostasis and inhibiting JNK1 activation and support the likely therapeutic value of the HBXIP/Nrf2 axis in breast cancer patients.

Acupuncture improved lipid metabolism by regulating intestinal absorption in mice

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, and its treatment remain a constant challenge. A number of clinical trials have shown that acupuncture treatment has beneficial effects for patients with NAFLD, but the molecular mechanisms underlying its action are still largely unknown. In this study, we established a mouse model of NAFLD by administering a methionine- and choline-deficient (MCD) diet and selected three acupoints (ST36, CV4, and KI1) or nonacupoints (sham) for needling. We then investigated the effects of acupuncture treatment on the progression of NAFLD and the underlying mechanisms. After two weeks of acupuncture treatment, the liver in the needling-nonapcupoint group (NG) mice appeared pale and yellowish in color, while that in the needling-acupoint group (AG) showed a bright red color. Histologically, fewer lipid droplets and inflammatory foci were observed in the AG liver than in the NG liver. Furthermore, the expression of proinflammatory signaling factors was significantly downregulated in the AG liver. A lipid analysis showed that the levels of triglyceride (TG) and free fatty acid (FFA) were lower in the AG liver than in the NG liver, with an altered expression of lipid metabolism-related factors as well. Moreover, the numbers of 8-hydroxy-2′-deoxyguanosine (8-OHdG)-positive hepatocytes and levels of hepatic thiobarbituric acid reactive substances (TBARS) were significantly lower in AG mice than in NG mice. In line with these results, a higher expressions of antioxidant factors was found in the AG liver than in the NG liver. Our results indicate that acupuncture repressed the progression of NAFLD by inhibiting inflammatory reactions, reducing oxidative stress, and promoting lipid metabolism of hepatocytes, suggesting that this approach might be an important complementary treatment for NAFLD.

Peroxiredoxin 4 (PRDX4), initially reported as an antioxidant, is overexpressed in lung cancer and participates in its progression. However, its role in the urethane-induced lung tumor model is undetermined. The aim of this study was to investigate the effect of PRDX4 overexpression on carcinogen-induced lung tumor development. Human PRDX4 overexpression transgenic (Tg) mice (hPRDX4^+/+) and non-Tg mice were intraperitoneally injected with urethane to induce lung tumor. After 6 months, tumor formation was compared between groups and possible mechanisms for the difference in tumor development were investigated. The serum and lung PRDX4 expressions were enhanced after urethane stimulation in Tg mice. Both the average number of tumors (0.5mm) and tumor diameter per mouse in the Tg group were significantly larger than in non-Tg controls, while body weight was lower in the Tg group. Compared with non-Tg controls, tumor cell proliferation was enhanced, while tumor cell apoptosis was suppressed in Tg mice. Systemic oxidative stress and oxidative stress in lung tumors were inhibited by PRDX4 overexpression. The balance of prooxidant enzymes and antioxidant enzymes was also shifted to a decreased level in Tg tumor. In lung tumor tissue, the density of microvessel penetrated into tumor was higher in the Tg group; macrophage infiltration was enhanced in Tg tumors, while there was no difference in T lymphocyte infiltration; the expressions of cytokines, including interleukin-1 beta (IL-1β) and matrix metallopeptidase 9 (MMP9), were elevated in Tg tumors, which resulted from enhanced phosphorylation of nuclear factor-κB p65 (NF-κB p65) and c-Jun, respectively. In conclusion, PRDX4 overexpression modulated tumor microenvironment and promoted tumor development in the mouse urethane-induced lung cancer model.

Background: Oxidative stress plays key roles in the progression of lung adenocarcinoma. Recently, we reported that peroxiredoxin 4 (PRDX4), an antioxidant enzyme, can be a prognostic marker of lung adenocarcinoma (LUAD). In the present study, we aimed to further investigate the relationship among the PRDX4 expression, epidermal growth factor receptor (EGFR) mutations and cell proliferation in LUAD.