Cancer cachexia is a progressive and multi-factorial metabolic syndrome characterized by loss of adipose tissue and skeletal muscle. White adipose tissue (WAT) lipolysis and white-to-brown transdifferentiation of WAT (WAT browning) are proposed to contribute to WAT atrophy in cancer cachexia. Chronic inflammation, mediated by cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), has been reported to promote cancer cachexia. However, whether chronic inflammation promotes cancer cachexia by regulating WAT metabolism and the underlying mechanism remains unclear. In this study, we first analyzed the association between chronic inflammation and WAT metabolism in gastric and colorectal cancer cachectic patients. In cachectic mice treated with anti-IL-6 receptor antibody, we clarified whether WAT lipolysis and browning were regulated by IL-6. Clinical analyses showed positive significant association between serum IL-6 and free fatty acid (FFA) both in early- and late-stage cancer cachexia. However, serum TNF-α was positively associated with serum FFA in the early- but not late-stage cachexia. WAT lipolysis was increased in early- and late-stage cachexia, while WAT browning was detected only in late-stage cachexia. Anti-IL-6 receptor antibody inhibited WAT lipolysis and browning in cachectic mice. Based on these findings, we conclude that chronic inflammation (especially that mediated by IL-6) might promote cancer cachexia by regulating WAT lipolysis in early-stage cachexia and browning in late-stage cachexia.

Muscle atrophy F-Box (MAFbx)/atrogin-1 and muscle ring-finger-1 (MuRF-1) have been identified as two muscle-specific E3 ubiquitin ligases that are highly expressed in skeletal muscle during muscle atrophy. However, the role of muscle-specific E3 ubiquitin ligases during the process of muscle atrophy of cancer cachexia remains largely unknown. In the present study, we analyzed the expression of atrogin-1 and MuRF-1 in the skeletal muscle of patients with malignant and benign disease. The possible mechanisms were studied both in a colon 26-induced cancer cachexia mouse model and in tumor necrosis factor-α (TNF-α) induced atrophy C2C12 cells. Our results demonstrated that atrogin-1 and MuRF-1 tended to be increased in the skeletal muscle of patients with malignant disease even before weight loss. Non-tumor body weights and gastrocnemius weights were significantly decreased while expression levels of ubiquitin proteasome pathway associated genes (atrogin-1, MuRF-1, ubiquitin and E2-14K) were upregulated in cancer cachexia mice. Significant myotube atrophy with atrogin-1 overexpression was observed in the C2C12 cells treated with TNF-α. Meanwhile, knockdown of atrogin-1 by small interfering RNA (siRNA) protected C2C12 cells from the adverse effect of TNF-α. In conclusion, muscle-specific E3 ubiquitin ligases were upregulated during cancer cachexia, and atrogin-1 may be a potential molecular target for treating muscle atrophy induced by cancer cachexia.

Consumption of dietary fat has been reported to be associated with gastric cancer risk, but the results of epidemiologic studies remain inconsistent. We conducted a meta-analysis to summarize the evidence regarding the association between dietary fat intake and gastric cancer risk. A comprehensive search of PubMed and EMBASE was performed to identify observational studies providing quantitative estimates between dietary fat and gastric cancer risk. Random effects model was used to calculate the summary relative risk(SRR) in the highest versus lowest analysis. Categorical dose-response analysis was conducted to quantify the association between dietary fat intake and gastric cancer risk. Heterogeneity among studies was evaluated using I² and tau2(between study variance)statistics. Subgroup analysis and publication bias analysis were also performed. Twenty-two articles were included in the meta-analysis. The SRR for gastric cancer was 1.18 for individuals with highest intake versus lowest intake of total fat (95% confidence interval [CI]: 0.999–1.39; n = 28; P< 0.001; tau² = 0.12; I² = 69.5%, 95% CI: 55%-79%) and 1.08 with a daily increase in total fat intake (20 g/d) (95%CI: 1.02–1.14; n = 6; P = 0.09; tau² = 0.002; I² = 46.8%, 95% CI: 0%-79%). Positive association between saturated fat intake (SRR = 1.31; 95%CI: 1.09–1.58;n = 18;P<0.001; tau² = 0.08; I² = 60.6%, 95% CI: 34%-76%), inverse association between polyunsaturated fat intake (SRR = 0.77; 95%CI: 0.65–0.92; n = 16; P = 0.003; tau² = 0.06; I² = 56.2%, 95% CI: 23%-75%) and vegetable fat intake (SRR = 0.55; 95%CI: 0.41–0.74; n = 4;P = 0.12; tau² = 0.04; I² = 48.6%, 95% CI: 0%-83%), and no association between monounsaturated fat intake (SRR = 1.00; 95%CI: 0.79–1.25; n = 14; P< 0.001; tau² = 0.10; I² = 63.0%, 95% CI: 34%-79%) and animal fat intake (SRR = 1.10; 95%CI: 0.90–1.33; n = 6; P = 0.13;tau² = 0.02; I² = 42.0%, 95% CI: 0%-70%) and gastric cancer risk were observed. Our results suggest that intake of total fat is potentially positively associated with gastric cancer risk, and specific subtypes of fats account for different effects. However, these findings should be confirmed by further well-designed cohort studieswith detailed dietary assessments and strict control of confounders.