Rui Hua Xu

Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism

Cancer cells exhibit increased glycolysis for ATP production due, in part, to respiration injury (the Warburg effect). Because ATP generation through glycolysis is less efficient than through mitochondrial respiration, how cancer cells with this metabolic disadvantage can survive the competition with other cells and eventually develop drug resistance is a long-standing paradox. We report that mitochondrial respiration defects lead to activation of the Akt survival pathway through a novel mechanism mediated by NADH. Respiration-deficient cells (ρ-) harboring mitochondrial DNA deletion exhibit dependency on glycolysis, increased NADH, and activation of Akt, leading to drug resistance and survival advantage in hypoxia. Similarly, chemical inhibition of mitochondrial respiration and hypoxia also activates Akt. The increase in NADH caused by respiratory deficiency inactivates PTEN through a redox modification mechanism, leading to Akt activation. These findings provide a novel mechanistic insight into the Warburg effect and explain how metabolic alteration in cancer cells may gain a survival advantage and withstand therapeutic agents.

Elevated neutrophil to lymphocyte ratio predicts survival in advanced pancreatic cancer

Background: Elevated neutrophil to lymphocyte ratio (NLR) is linked with worse survival in many malignancies, whereas its association with pancreatic cancer (PC) remains unclear. Methods: We retrospectively reviewed 95 patients with locally advanced or metastatic PC receiving gemcitabine-based chemotherapy. The prognostic value of NLR was evaluated. Results: Elevated pretreatment NLR (>5) was observed in 16 out of 89 eligible patients, which was identified as an independent prognostic factor for overall survival (OS). The median OS for patients with elevated and normal NLR were 2.4 months and 7.7 months, respectively (p <0.001). Conclusions: Elevated NLR is a predictor of shorter survival in patients with advanced PC.

High incidence of hepatitis B virus infection in B-cell subtype non-Hodgkin lymphoma compared with other cancers

The authors investigated the prevalence of hepatitis B virus (HBV) infection by using serologic markers in non‐Hodgkin lymphoma (NHL) compared with other types of cancers in Chinese patients.

Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial

The efficacy and safety of bevacizumab with modified irinotecan, leucovorin bolus, and 5-fluorouracil intravenous infusion (mIFL) in the first-line treatment of metastatic colorectal cancer (mCRC) has not been well evaluated in randomized clinical trials in Chinese patients. We conducted a phrase III trial in which patients with previously untreated mCRC were randomized 2:1 to the mIFL [irinotecan (125 mg/m2), leucovorin (20 mg/m2) bolus, and 5-fluorouracil intravenous infusion (500 mg/m2) weekly for four weeks every six weeks] plus bevacizumab (5 mg/kg every two weeks) group and the mIFL group, respectively. Co-primary objectives were progression-free survival (PFS) and 6-month PFS rate. In total, 214 patients were enrolled. Our results showed that addition of bevacizumab to mIFL significantly improved median PFS (4.2 months in the mIFL group vs. 8.3 months in the bevacizumab plus mIFL group, P < 0.001), 6-month PFS rate (25.0% vs. 62.6%, P < 0.001), median overall survival (13.4 months vs. 18.7 months, P = 0.014), and response rate (17% vs. 35%, P = 0.013). Grades 3 and 4 adverse events included diarrhea (21% in the mIFL group and 26% in the bevacizumab plus mIFL group) and neutropenia (19% in the mIFL group and 33% in the bevacizumab plus mIFL group). No wound-healing complications or congestive heart failure occurred. Our results suggested that bevacizumab plus mIFL is effective and well tolerated as first-line treatment for Chinese patients with mCRC. Clinical benefit and safety profiles were consistent with those observed in pivotal phase III trials with mainly Caucasian patients.

Overexpression of paxillin induced by miR-137 suppression promotes tumor progression and metastasis in colorectal cancer

The deregulation of paxillin (PXN) has been involved in the progression and metastasis of different malignancies including colorectal cancer (CRC). miR-137 is frequently suppressed in CRC. PXN is predicted to be a direct target of miR-137 in CRC cells. On this basis, we hypothesized that overexpression of PXN induced by suppression of miR-137 may promote tumor progression and metastasis and predicts poor prognosis. We detected the expression of PXN and miR-137 in clinical tumor tissues by immunohistochemical analysis and real-time PCR, positive PXN staining was observed in 198 of the 247 (80.1%) cases, whereas no or weak PXN staining was observed in the adjacent non-cancerous area. Higher level of PXN messenger RNA (mRNA) and lower level of miR-137 was observed in cancer tissues than adjacent non-cancerous tissues. High expression of PXN and low expression of miR-137 was associated with aggressive tumor phenotype and adverse prognosis. Moreover, the expression of PXN was negatively correlated with miR-137 expression. A dual-luciferase reporter gene assay validated that PXN was a direct target of miR-137. The use of miR-137 mimics or inhibitor could decrease or increase PXN mRNA and protein levels in CRC cell lines. Knockdown of PXN or ectopic expression of miR-137 could markedly inhibit cell proliferation, migration and invasion in vitro and repress tumor growth and metastasis in vivo. Taken together, these results demonstrated that overexpression of PXN induced by suppression of miR-137 promotes tumor progression and metastasis and could serve as an independent prognostic indicator in CRC patients.

ABO blood group, hepatitis B viral infection and risk of pancreatic cancer

Little is known about the role of association between ABO blood type and risk of pancreatic cancer develops through effects on hepatitis B viral (HBV) infection. Our study aimed to determine whether joint ABO blood type and HBV infection could increase the risk for pancreatic cancer. A total of 645 patients with pancreatic adenocarcinoma and 711 age‐ and sex‐matched individuals who had nonmalignant diseases treated at the Sun Yat‐sen University Cancer Center in China were retrospectively analyzed. Blood samples were tested for ABO blood type and hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti‐HBs), hepatitis B e antigen (HBeAg), hepatitis B e antibody (anti‐HBe) and hepatitis B core antibody (anti‐HBc). Multivariable unconditional logistic regression analysis was used to estimate adjusted odds ratios [AORs] and 95% confidence interval [CI]. Multivariable analysis with adjustment for risk factors showed that A blood type, HBsAg‐positive/anti‐HBc‐positive, anti‐HBs‐positive/anti‐HBc‐positive were significantly associated with pancreatic cancer. The estimated AORs (95% CI) were as follows: A blood type, 1.425 (1.071–1.894), HBsAg‐positive/anti‐HBc‐positive, 1.610 (1.125–2.304), anti‐HBs‐positive/anti‐HBc‐positive, 1.526 (1.159–2.011). The effect of A blood type significantly modified the risk of pancreatic cancer among subjects with anti‐HBc‐positive (AORs = 1.882, 95% CI, 1.284–2.760). In our study, we reported an association between A blood type, infection with HBV and pancreatic cancer risk. Moreover, we found a synergism between A blood type and HBV infection in the development of pancreatic cancer.

Effective elimination of cancer stem cells by a novel drug combination strategy

Development of effective therapeutic strategies to eliminate cancer stem cells, which play a major role in drug resistance and disease recurrence, is critical to improve cancer treatment outcomes. Our study showed that glioblastoma stem cells (GSCs) exhibited low mitochondrial respiration and high glycolytic activity. These GSCs were highly resistant to standard drugs such as carmustine and temozolomide (TMZ), but showed high sensitivity to a glycolytic inhibitor 3‐bromo‐2‐oxopropionate‐1‐propyl ester (3‐BrOP), especially under hypoxic conditions. We further showed that combination of 3‐BrOP with carmustine but not with TMZ achieved a striking synergistic effect and effectively killed GSCs through a rapid depletion of cellular ATP and inhibition of carmustine‐induced DNA repair. This drug combination significantly impaired the sphere‐forming ability of GSCs in vitro and tumor formation in vivo, leading to increase in the overall survival of mice bearing orthotopic inoculation of GSCs. Further mechanistic study showed that 3‐BrOP and carmustine inhibited glyceraldehyde‐3‐phosphate dehydrogenase and caused a severe energy crisis in GSCs. Our study suggests that GSCs are highly glycolytic and that certain drug combination strategies can be used to effectively overcome their drug resistance based on their metabolic properties. STEM Cells2013;31:23–34

Identification of MicroRNA-214 as a negative regulator of colorectal cancer liver metastasis by way of regulation of fibroblast growth factor receptor 1 expression

The purpose of this study was to identify microRNAs (miRNAs) involved in the pathology of colorectal cancer (CRC) liver metastasis and investigate their underlying mechanisms. A total of 39 miRNAs were identified to be differentially expressed between 16 primary CRC tissues with liver metastases and 16 CRC tissues without liver metastases from 32 patients by Affymetric miRNA microarrays. A panel of eight miRNAs were confirmed to be significantly and differentially expressed between CRC tissues with and without liver metastases through quantitative reverse‐transcription polymerase chain reaction (RT‐PCR) analysis in the 32 patients. In a validated cohort of 99 CRC patients (44 with and 55 without liver metastases), only miR‐214 was validated to be significantly down‐regulated in CRC with liver metastases, which was associated with an unfavorable prognosis. Ectopic expression of miR‐214 suppressed proliferation, migration, and invasion in vitro, tumor growth and liver metastasis in an in vivo xenograft mouse model, whereas miR‐214 knockdown promoted proliferation, migration, and invasion in CRC cell lines. Further studies indicated that fibroblast growth factor receptor 1 (FGFR1) was a potential target of miR‐214. Restoring miR‐214 expression in CRC cells decreased endogenous FGFR1 messenger RNA (mRNA) and protein levels. FGFR1 knockdown mimicked the tumor suppressive effect of miR‐214 on CRC cells, while reintroduction of FGFR1 abolished the tumor suppressive effect of miR‐214 on CRC cells. Moreover, miR‐214 expression levels were inversely correlated with FGFR1 in CRC patients. Conclusion: Down‐regulation of miR‐214 expression was correlated with increased FGFR1 expression levels, which may contribute to increased CRC liver metastasis. miR‐214 may serve as a potential marker to predict survival, and the miR‐214‐FGFR1 axis may be a therapeutic target in CRC patients. (Hepatology 2014;60:598–609)

Long non-coding RNA XIST regulates gastric cancer progression by acting as a molecular sponge of miR-101 to modulate EZH2 expression

BackgroundLong non-coding RNAs (lncRNAs) have emerged as critical regulators of tumor progression. However, the role and molecular mechanism of lncRNA XIST in gastric cancer is still unknown.MethodsReal-time PCR analysis was performed to measure the expression levels of lncRNA XIST in gastric cancer tissues and cell lines, the correlation between lncRNA XIST expression and clinicopathological characteristics and prognosis was analyzed in gastric cancer patients. The biological function of lncRNA XIST on gastric cancer cells were determined both in vitro and in vivo. The regulating relationship between lncRNA XIST and miR-101 was investigated in gastric cancer cells.ResultslncRNA XIST was significantly up-regulated in gastric cancer tissues and cell lines. Overexpression of lncRNA XIST was markedly associated with larger tumor size, lymph node invasion, distant metastasis and TNM stage in gastric cancer patients. Functionally, knockdown of lncRNA XIST exerted tumor-suppressive effects by inhibiting cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo. Furthermore, an inverse relationship between lncRNA XIST and miR-101 was found. Polycomb group protein enhancer of zeste homolog 2 (EZH2), a direct target of miR-101, could mediated the biological effects that lncRNA XIST exerted.ConclusionslncRNA XIST is up-regulated and is associated with aggressive tumor phenotypes and patient survival in gastric cancer, and the newly identified lncRNA XIST/miR-101/EZH2 axis could be a potential biomarkers or therapeutic targets for gastric cancer patients.

Comparison of 6th and 7th AJCC TNM Staging Classification for Carcinoma of the Stomach in China

BackgroundThe 7th edition of American Joint Committee on Cancer tumor-node-metastasis (AJCC TNM) staging system was put into use recently. The study aimed to evaluate its predictive ability on survival and compare the difference between the 6th and 7th editions of AJCC TNM system in gastric carcinoma.Materials and MethodsA total of 1000 gastric carcinoma patients receiving treatment in our center were selected for the analysis. Patients were staged using both the 6th and 7th editions AJCC TNM staging system. Survival analysis was performed with a Cox regression model.ResultsOf previous stage IV patients, 39.9% (112 of 281) migrated to a lower tier in the 7th edition. By setting the cutoff of positive lymph nodes as 0, 2, 6, and 15, the 7th edition strengthens the role of positive lymph nodes. Multivariable regression analysis showed that both 6th and 7th TNM stage systems were independent factors for overall survival. For lymph nodes negative patients, the 5-year overall survival for patients with fewer than 15 resected lymph nodes was significantly lower than those with more than 15.ConclusionsAJCC 7th is not superior to AJCC 6th in predicting the 5-year overall survival rates of gastric adenocarcinoma patients. The definition of stage IV and the selection of cutoffs for MLNC in the AJCC 7th system is much more reasonable compared with the AJCC 6th system.