CIZ1 aggravates gastric cancer progression via mediating FBXL19-AS1 and miR-339-3p.

Gastric cancer (GC) remains a prevalent malignancy with high morbidity and mortality. CDKN1A interacting zinc finger protein 1 (CIZ1) has been demonstrated to have oncogenic functions in the development of cancers. We detected CIZ1 expression via quantitative real-time PCR (RT-qPCR). The protein level of CIZ1 was measured through Western blot. We noticed that CIZ1 expression was markedly enhanced in GC cells. Furthermore, functional experiments including colony formation assay, EdU staining assay, transwell assay, TUNEL staining assay and flow cytometry analysis uncovered that CIZ1 silencing attenuated cell malignant phenotypes in GC. Through bioinformatics tools and mechanism assays, we explored the up-stream mechanism of CIZ1 and determined that CIZ1 was modulated by FBXL19 antisense RNA 1 (FBXL19-AS1) and microRNA-339-3p (miR-339-3p). Additionally, miR-339-3p exerted a negative role on GC development in vitro, and FBXL19-AS1 depletion also had the inhibitory impacts on the progression of GC in vitro. Eventually, the finding that CIZ1 overexpression reversed the effects of FBXL19-AS1 silencing on GC development was validated by rescue assays. In a word, CIZ1 functioned as a tumor promoter in GC, indicating that CIZ1 might be a promising target for GC treatment.

Pantoprazole blocks the JAK2/STAT3 pathway to alleviate skeletal muscle wasting in cancer cachexia by inhibiting inflammatory response.

OBJECTIVE: Cancer cachexia is often present in patients with advanced malignant tumors, and the subsequent body weight reduction results in poor quality of life. However, there has been no progress in developing effective clinical therapeutic strategies for skeletal muscle wasting in cancer cachexia. Herein, we explored the functions of pantoprazole on cancer cachexia skeletal muscle wasting. METHODS: The mouse colon adenocarcinoma cell line C26 was inoculated in the right forelimb of male BALB/C mice to establish a cancer cachexia model. The animals were treated with or without different concentrations of pantoprazole orally, and the body weight, tumor growth, spontaneous activity, and muscle functions were determined at various time points. Two weeks later, the levels of serum IL-6 and TNF-α, the mRNA levels of gastrocnemius JAK2 and STAT3, and the expression levels of p-JAK2, p-STAT3, Fbx32, and MuRF1 were examined with ELISA assay, qRT-PCR assay, and Western blotting, respectively. Further studies were performed to assess the levels of Fbx32 and MuRF1 expression and morphological changes. RESULTS: Pantoprazole can alleviate cancer cachexia-induced body weight reduction and inhibit skeletal muscle wasting in a dose-dependent manner. Our results indicated that pantoprazole treatment can decrease the levels of serum IL-6 and TNF-α (56.3% and 67.6%, respectively), and inhibit the activation of the JAK2/STAT3 signaling pathway. Moreover, the expression levels of MuRF1 and Fbx32 were also suppressed after pantoprazole treatment. CONCLUSION: Our findings suggested that pantoprazole can alleviate cancer cachexia skeletal muscle wasting by inhibiting the inflammatory response and blocking the JAK2/STAT3 or ubiquitin proteasome pathway.

Aliskiren targets multiple systems to alleviate cancer cachexia.

To examine the effects of aliskiren, a small-molecule renin inhibitor, on cancer cachexia and to explore the underlying mechanisms. A cancer cachexia model was established by subcutaneously injecting C26 mouse colon carcinoma cells into isogenic BALB/c mice. Aliskiren was administered intragastrically [10 mg/kg body weight (BW)] on day 5 (as a preventive strategy, AP group) or on day 12 (as a therapeutic strategy, AT group) after C26 injection. Mice that received no C26 injection (healthy controls, HC group) or only C26 injection but not aliskiren (cancer, CA group) were used as controls. BW, tumor growth, whole body functions, and survival were monitored daily in half of the mice in each group, whereas serum, tumors, and gastrocnemius muscles were harvested from the other mice after sacrifice on day 20 for further analysis. Aliskiren significantly alleviated multiple cachexia­associated symptoms, including BW loss, tumor burden, muscle wasting, muscular dysfunction, and shortened survival. On the molecular level, aliskiren antagonized cachexia­induced activation of the renin­angiotensin system (RAS), systematic and muscular inflammation, oxidative stress, and autophagy­lysosome as well as ubiquitin­proteasome stimulation. In addition, early administration of aliskiren before cachexia development (AP group) resulted in more robust effects in alleviating cachexia or targeting underlying mechanisms than administration after cachexia development (AT group). Aliskiren exhibited potent anti­cachexia activities. These activities were achieved through the targeting of at least four mechanisms underlying cachexia development: RAS activation, increase in systematic inflammation, upregulation of oxidative stress, and stimulation of autophagy-lysosome pathway (ALP) and ubiquitin-proteasome pathway (UPP).

Combined treatment of carfilzomib and z-VAD-fmk inhibits skeletal proteolysis and apoptosis and ameliorates cancer cachexia.

The purpose of the study was to evaluate the therapeutic benefit of treatments with carfilzomib (CFZ) and z-VAD-fmk in a mouse model of cancer-induced cachexia. The model of cancer-associated cachexia was generated by injecting murine C26 adenocarcinoma cells into BALB/C mice. CFZ and z-VAD-fmk were administered individually or in combination at 5 and 12 days after inoculation. Changes in body weight, gastrocnemius muscle mass, tumor burden, spontaneous activity, survival, and metabolic profiles were noted. Also evaluated were the circulatory levels of renin and angiotensin II, and levels of apoptotic, proteolytic, and renin-angiotensin system-associated markers and transcription factor 2 (ATF2) in gastrocnemius muscle. The CFZ and z-VAD-fmk treatments were associated with less muscle wasting, reduced tumor burden, modulated metabolism, higher levels of glucose, albumin, and total proteins, and lower levels of triglyceride fatty acids, more spontaneous physical activity, and longer survival in C26-inoculated mice compared with PBS-treated cachectic mice. CFZ and z-VAD-fmk treatments resulted in higher levels of caspase-3 and BAX and lower level of BCL-XL in gastrocnemius muscles and altered the level of proteins in the renin-angiotensin system. The combined treatment administered 5 days after C26 inoculation was more effective than other regimens. Combined treatment with CFZ and z-VAD-fmk early in the development of cachexia was associated with signs of less proteolysis and apoptosis and less severe cachexia in a mouse model of cancer-induced cachexia.