BCL-2 family proteins regulate the mitochondrial apoptotic pathway. BOK, a multidomain BCL-2 family protein, is generally believed to be an adaptor protein similar to BAK and BAX, regulating the mitochondrial permeability transition during apoptosis. Here we report that BOK is a positive regulator of a key enzyme involved in uridine biosynthesis; namely, uridine monophosphate synthetase (UMPS). Our data suggest that BOK expression enhances UMPS activity, cell proliferation, and chemosensitivity. Genetic deletion of Bok results in chemoresistance to 5-fluorouracil (5-FU) in different cell lines and in mice. Conversely, cancer cells and primary tissues that acquire resistance to 5-FU down-regulate BOK expression. Furthermore, we also provide evidence for a role for BOK in nucleotide metabolism and cell cycle regulation. Our results have implications in developing BOK as a biomarker for 5-FU resistance and have the potential for the development of BOK-mimetics for sensitizing 5-FU-resistant cancers.

Transforming growth factor beta (TGF-β) is crucial for transdifferentiation of hepatic stellate cells (HSCs) and the blunting of TGF-β signaling in HSCs can effectively prevent liver fibrosis. Krüppel-like factor 11 (KLF11) is an early response transcription factor that potentiates TGF-β/Smad signaling by suppressing the transcription of inhibitory Smad7. Using a mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis, we observed significant upregulation of KLF11 in the activated HSCs during liver fibrogenesis. Meanwhile, the downregulation of miR-30 was observed in the HSCs isolated from fibrotic liver. Adenovirus-mediated ectopic expression of miR-30 was under the control of smooth muscle α-actin promoter, showing that the increase in miR-30 in HSC greatly reduced CCl4-induced liver fibrosis. Subsequent investigations showed that miR-30 suppressed KLF11 expression in HSC and led to a significant upregulation of Smad7 in vivo. Mechanistic studies further confirmed that KLF11 was the direct target of miR-30, and revealed that miR-30 blunted the profibrogenic TGF-β signaling in HSC by suppressing KLF11 expression and thus enhanced the negative feedback loop of TGF-β signaling imposed by Smad7. Finally, we demonstrated that miR-30 facilitated the reversal of activated HSC to a quiescent state as indicated by the inhibition of proliferation and migration, the loss of activation markers, and the gain of quiescent HSC markers. In conclusion, our results define miR-30 as a crucial suppressor of TGF-β signaling in HSCs activation and provide useful insights into the mechanisms underlying liver fibrosis.

Hepatocyte death, as well as the following inflammatory and fibrogenic signaling cascades, is the key trigger of liver fibrosis. Here, we isolated hepatocytes from CCl4-induced fibrotic liver and found that hepatocyte lincRNA-p21 significantly increased during liver fibrosis. The increase of hepatocyte lincRNA-p21 was associated with the loss of miR-30, which can inhibit TGF-β signaling by targeting KLF11. We revealed that lincRNA-p21 modulated miR-30 availability by acting as a competing endogenous RNA (ceRNA). The physiological significance of this interaction is highlighted by the feedback loop, in which lincRNA-p21 works as a downstream effector of the TGF-β signaling to strengthen TGF-β signaling and mediate its role in promoting liver fibrosis by interacting with miR-30. In vivo results showed that knockdown of hepatocyte lincRNA-p21 greatly reduced CCl4-induced liver fibrosis and inflammation, whereas ectopic expression of miR-30 in hepatocyte exhibited the similar results. Mechanistic studies further revealed that inhibition of miR-30 impaired the effects of lincRNA-p21 on liver fibrosis. Additionally, lincRNA-p21 promoted hepatocyte apoptosis in vitro and in vivo, whereas the proliferation rate of hepatocyte was suppressed by lincRNA-p21. The pleiotropic roles of hepatocyte lincRNA-p21 suggest that it may represent an unknown paradigm in liver fibrosis and serve as a potential target for therapy.

Cancer cachexia is a common condition in many cancer patients, particularly those with advanced disease. Cancer cachexia patients are generally less tolerant to chemotherapies and radiotherapies, largely limiting their treatment options. While the search for treatments of this condition are ongoing, standards for the efficacy of treatments have yet to be developed. Current diagnostic criteria for cancer cachexia are primarily based on loss of body mass and muscle function. However, these criteria are rather limiting, and in time, when weight loss is noticeable, it may be too late for treatment. Consequently, biomarkers for cancer cachexia would be valuable adjuncts to current diagnostic criteria, and for assessing potential treatments. Using high throughput methods such as “omics approaches”, a plethora of potential biomarkers have been identified. This article reviews and summarizes current studies of biomarkers for cancer cachexia.

Background Cachexia, a complex multi-organ syndrome, shortens survival time of patients, particularly those with cancer. Many studies and clinical trials have been carried out to identify cachexia-inducing factors and potential treatments for cancer cachexia over the last 20 years. Of these factors, some are promising targets for treatment in humans, owing to their expression profiles in patients. Several clinical interventions, which act on either cachexia-inducing factors or tissues affected by cachexia, have been developed. Some have had positive effects in the treatment of cancer cachexia; however, the question remains whether these interventions reverse cancer cachexia and could be used as standard interventions for disease treatment. The aim of this review is to understand the basic mechanisms and factors that induce cancer cachexia and their efficacies in clinical trials, providing a better outlook for future studies of cancer cachexia. Methods A systematic search was performed using PubMed and ClinicalTrials.gov databases for cachexia mediators and clinical trials. Results Of all databases and peer-reviewed facts considered, 256 papers and 35 clinical trials were included in this systematic review. Twenty-one mediators were identified, and 17 clinical interventions were reported in these studies. Outcomes of these clinical trials were assessed on changes in overall survival, body weight, lean body mass, appetite, muscle strength, muscle function, quality of life, and cytokine levels. Conclusions There is no current standard or successful intervention for treating cancer cachexia. Further research is needed to improve our understanding of initiators of cachexia to achieve successful outcomes in cachexia clinical trials.