Mitofusin-2 prevents skeletal muscle wasting in cancer cachexia.

Cancer cachexia remains a leading cause of morbidity and mortality worldwide, despite extensive research and clinical trials. The prominent clinical feature of cancer cachexia is the continuous loss of skeletal muscle that cannot be fully reversed by conventional nutritional support, and that leads to progressive functional impairment. The mechanism underlying muscle loss in patients with cachexia is poorly understood. The present study analyzed 21 cancer patients with or without cachexia, and demonstrated that mitofusin-2 (Mfn2) was downregulated in the rectus abdominis of patients with cachexia, which was associated with body weight loss. In vitro cell experiments indicated that loss of Mfn2 was associated with atrophy of the C2C12 mouse myoblast cell line. Furthermore, in vivo animal experiments demonstrated that cachexia decreased gastrocnemius muscle mass and Mfn2 expression, and overexpression of Mfn2 in gastrocnemius muscle was able to partially attenuate cachexia-induced gastrocnemius muscle loss. The results of the present study suggested that Mfn2 is involved in cachexia-induced muscle loss and may serve as a potential target for therapy of cachexia.

The Effect of Silencing HIF-1α Gene in BxPC-3 Cell Line on Glycolysis-Related Gene Expression, Cell Growth, Invasion, and Apoptosis.

Hypoxia has been proved to be a typical character of solid tumors. Tumor cells prefer to use glucose through the glycolysis pathway instead of aerobic respiration. However, the precise molecular mechanism underlying this so-called Warburg effect remains elusive. In the current study, siRNA was synthesized and transfected into BxPC-3 cell line to silence the expression of HIF-1α gene. It was found that hypoxia induced hypoxia-inducible factor 1α (HIF-1α) overexpression in BxPC-3 cells, enhanced the expression of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase A, thus facilitating glycolysis and making tumor cells more tolerant to hypoxic stress. The silencing of HIF-1α gene significantly attenuated glycolysis under hypoxic conditions, inhibited the growth and invasion ability of BxPC-3 cells, and enhanced hypoxia-induced cell apoptosis.

quantitative assessment of the influence of cytochrome P450 1A2 gene polymorphism and colorectal cancer risk.

Cytochrome P450 1A2 (CYP1A2) encodes a member of the cytochrome P450 superfamily of enzymes, which play a central role in activating and detoxifying many carcinogens and endogenous compounds thought to be involved in the development of colorectal cancer (CRC). The CYP1A2*C (rs2069514) and CYP1A2*F (rs762551) polymorphism are two of the most commonly studied polymorphisms of the gene for their association with risk of CRC, but the results are conflicting. To derive a more precise estimation of the relationship between CYP1A2 and genetic risk of CRC, we performed a comprehensive meta-analysis which included 7088 cases and 7568 controls from 12 published case-control studies. In a combined analysis, the summary per-allele odds ratio for CRC was 0.91 (95% CI: 0.83-1.00, P = 0.04), and 0.91 (95% CI: 0.68-1.22, P = 0.53), for CYP1A2 *F and *C allele, respectively. In the subgroup analysis by ethnicity, significant associations were found in Asians for CYP1A2*F and CYP1A2*C, while no significant associations were detected among Caucasian populations. Similar results were also observed using dominant genetic model. Potential sources of heterogeneity were explored by subgroup analysis and meta-regression. No significant heterogeneity was detected in most of comparisons. This meta-analysis suggests that the CYP1A2 *F and *C polymorphism is a protective factor against CRC among Asians.

[Proteolysis induce factor in the digestive systematic cancer cachexia patients: its expression and role in cancer cachexia].

OBJECTIVE: To demonstrate the expression of proteolysis induce factor(PIF) in the gastrointestinal(GI) cancer cachexia patients and evaluate its role in cancer cachexia. METHODS: Examination of PIF was performed in urine samples from 28 GI cancer cachexia patients, 13 GI cancer patients without cachexia, and 12 weight loss patients with benign disease. PIF was added to the mice cultured C2C12 muscle cells, then the protein kinase B(Akt) phosphorylation and morphological change were measured. RESULTS: The positive rate of PIF in urine of 28 cancer cachexia patients was 53.6%(15/28). In the other two groups, no positive result was detected. PIF could successfully induce Akt phosphorylation, cell atrophy, metamorphosis, and death. The peak of this phosphorylation could be detected after half an hour of the initiation of PIF at a concentration of 4 nmol/L. CONCLUSIONS: PIF is specifically and highly expressed in GI cancer cachexia patients' urine. PIF can induce cancer cachexia possibly by activating Akt phosphorylation and inducing downstream proteolysis.

Differential gene expression of Wnt signaling pathway in benign, premalignant, and malignant human breast epithelial cells.

To gain insight into the role of gene expression alterations in breast cancer progression, we conducted a comprehensive gene expression analysis of a series of cell lines derived from MCF10A, which include benign MCF10A cells, premalignant AT, and malignant CA1a tumor cells. We analyzed gene expression variation using the Agilent Human Genome Oligo Microarray with the goal of identifying gene-specific expression change events. In addition to a previously noted overexpression in oncogene MDM2, HRAS, and PCNA, our studies identified overexpression of Wnt signaling pathway in malignant breast cell lines. The Kaplan-Meier plot showed that high c-Myc expression in breast cancer was associated with tumor progression and the patient's poor survival. This study showed that the Wnt pathway has further provided a basis for the development of potential biomarker for breast cancer prognosis.

Pyruvate kinase type M2 is upregulated in colorectal cancer and promotes proliferation and migration of colon cancer cells.

Pyruvate kinase type M2 (PKM2) has been reported to be involved in aerobic glycolysis and cell growth in various tumors. However, the expression pattern of PKM2 in colorectal cancer (CRC) and the correlation between PKM2 expression and CRC remains unclear. The aim of this study is to investigate PKM2 expression and its possible role in CRC. We found that expression of PKM2 was increased in CRC and the increased PKM2 expression was associated with later stage and lymph metastasis of the tumors. Knockdown of PKM2 suppressed the aerobic glycolysis and decreased lactate production of colon cancer RKO cells. Knockdown of PKM2 repressed proliferation and migration of the cells. Inhibition of PKM2 suppressed xenograft tumor growth of RKO cells in vivo. These results suggest that the expression of PKM2 plays a critical role in development of CRC, and it may provide a growth advantage for colon cancer cells. Thus, PKM2 might be a potential therapeutic target for CRC.

Role of beta1-adrenoceptor in increased lipolysis in cancer cachexia.

Increased production of hormone-sensitive lipase (HSL) protein has been demonstrated to be the major cause behind enhanced lipolysis in cancer cachexia. The mechanism governing this alteration is unknown and was presently investigated. This study was conducted to detect the expression of relevant receptors in the adipocytes of cancer cachexia patients, and to elucidate their implication in the increased lipolysis. Gene expressions of beta1-adrenoceptor (ADRB1), beta2-adrenoceptor (ADRB2), beta3-adrenoceptor (ADRB3), alpha2C-adrenoceptor (ADRA2C), natriuretic peptide receptor A (NPRA), insulin receptor (INSR), and HSL were determined in adipose tissues of 34 patients by real-time PCR. Protein levels of ADRB1 and HSL were determined by western blot analysis. beta1-Adrenoceptor (ADRB1) was also detected by immunofluorescence staining. mRNA expressions of both ADRB1 and HSL were approximately 50% elevated selectively in the cachexia group, whereas mRNA levels of the other receptors were unchanged. beta1-Adrenoceptor (ADRB1) protein expression was 1.5-fold increased in cachexia as compared with the cancer controls, and 3-fold increased as compared with nonmalignant controls, and was confirmed as a membrane protein in adipocytes by immunofluorescence. Hormone-sensitive lipase (HSL) protein expression was 2-2.5-fold increased selectively in cachectic patients. There was a positive correlation between the protein expressions of ADRB1 and HSL. As much as approximately 50% of the variations in HSL protein expression could be explained by variations in ADRB1 protein expression. There was a link between ADRB1 protein level and lipolytic rate. Increased ADRB1 expression may account for some of the functional changes of HSL in patients with cancer cachexia.

Diagnostic methods for initial evaluation of primary gastrointestinal stromal tumors.

OBJECTIVE: To describe the imaging features of gastrointestinal stromal tumors (GISTs) at initial presentation with clinical, surgical, and pathologic correlation, and to evaluate values of various techniques in GISTs. METHODS: This retrospective study recruited 70 patients with histologically proved GISTs between December 2004, and May 2009 in the Department of General Surgery, Zhongshan Hospital, Fudan Univeristy, Shanghai, China. Each patient underwent CT scanning, 39 patients underwent simultaneous endoscopy, 12 patients underwent endoscopic ultrasound (EUS), and 36 patients underwent transabdominal ultrasonography (TAUS) simultaneously. Features of GISTs were assessed. RESULTS: Computerized tomography findings showed an eccentric mass in 44 patients, an intraluminal component in 24, and a transmural distribution in 2. Forty-two tumors were dumbbell-shaped, 2 were round, while 26 were irregular. Forty-three tumors presented with well-defined masses, while 27 with unclear borders. The arterial phase attenuation showed the continuous enhancement. The portal-venous phase attenuation was heterogeneous in 26 and homogeneous in the other 44. There was a significant correlation between certain CT features and tumor risk stratification. Gastrointestinal stromal tumors were characterized by a smooth shape and normal overlying mucosa in endoscopy, hypoechoic, and solid in TAUS. CONCLUSION: Imaging examinations are pivotal in the management of GISTs. The CT scan is valuable in the diagnosis, staging, and treatment planning of GISTs. Endoscopy and EUS contribute to the detection of mucosal lesions. Other methods including TAUS, fluorodeoxyglucose positron emission tomography, CT gastrography, and MRI help in specific cases.