Yuehong Cui

FOXO3a promotes gastric cancer cell migration and invasion through the induction of cathepsin L

Forkhead box O3A (FOXO3a) is an important transcription factor involved in various human cancers. However, the role of FOXO3a in regulating the invasion and metastasis of gastric cancer cells has not been clarified. Here, we report that FOXO3a overexpression promoted migration and invasion of gastric cancer cells by upregulating cathepsin L. FOXO3a knockdown suppressed migration and invasion and also downregulated cathepsin L expression in gastric cancer cells. Silencing cathepsin L in these cells suppressed FOXO3a overexpression-induced cell migration and invasion. Mechanistic studies revealed that FOXO3a increased cathepsin L promoter activation, and cathepsin L overexpression repressed E-cadherin expression, causing gastric cancer cells to undergo epithelial-mesenchymal transition (EMT). Our data reveal a previously unexplored function of FOXO3a in gastric cancer invasion by regulating proteins involved in extracellular matrix (ECM) degradation and EMT. We suggest that FOXO3a may be of prognostic value and a potential therapeutic target in blocking tumor metastasis.

Efficacy of trastuzumab beyond progression in HER2 positive advanced gastric cancer: a multicenter prospective observational cohort study

Introduction Trastuzumab plus chemotherapy is the standard first-line regimen in HER2 positive advanced gastric cancer (AGC), but lack of data in post-progression treatment. So, it is worth evaluating the efficacy of continuing trastuzumab after failure of the first-line trastuzumab based treatment. Methods 59 patients were enrolled from Zhongshan Hospital Fudan University, Sun Yat-sen University Cancer Center and Peking University Cancer Hospital between September 2012 and Oct 2015. Patients were divided into two groups according to the second line regimens: with or without trastuzumab. The primary endpoint was progression free survival of second line therapy (PFS2). Secondary end points included overall survival (OS), response rate, and adverse events (AEs). Results Baseline factors were well balanced between two groups. 32 patients treated with trastuzumab plus second line chemotherapy (group A) and 27 patients received chemotherapy alone (group B). The median follow-up time was 7.60 months (range 1.50-32.50). Longer median PFS2 was observed in group A than in group B (3.1 vs 2.0 months, P=0.008). There was no significant differences of median OS2 calculating from the second line therapy (10.5 vs 6.5 months, P=0.172) between two groups. Response rate was 9.3% in group A compared with 3.7% in group B (P=0.617). AEs were similar in two groups including cardiac safety. Subgroup analysis showed that factors of male, age<65, good performance status, HER2 immunohistochemical (IHC) 2+ and poor response to first line indicated superior PFS2 in patients continuing trastuzumab to those treated with chemotherapy alone. Conclusion Continuing treatment of trastuzumab beyond first line therapy progression showed effective and safe in AGC.

Five Cases Report of Solid Tumor Synchronously with Hematologic Malignancy

The reported incidence of synchronous multiple primary cancer (SMPC) is rare, and it is even less common to observe synchronous solid tumor with a hematological malignancy. We report five cases of solid tumor presented synchronously with hematological malignancy, all observed within a 2 year period at the oncology department of a university hospital in Shanghai, China. These individual cases included lung adenocarcinoma with chronic myelogenous leukemia, colon cancer with solitary plasmocytoma, gastric adenocarcinoma with diffuse large B cell non-Hodgkins lymphoma, lung adenocarcinoma with multiple myeloma, and colon cancer with diffuse large B cell non-Hodgkins lymphoma. It is challenging to therapeutically control the biological behavior of concurrent multiple primary tumors, and there is no standard treatment for such rare conditions. In this paper we discuss these five cases of SMPC and their treatments.

Lentiviral-mediated siRNA targeted against osteopontin suppresses the growth and metastasis of gastric cancer cells

The expression of osteopontin (OPN) has been correlated with tumor growth and metastasis. However, the mechanisms by which OPN promotes tumor metastasis remain unclear. In this study, we aimed to investigate the anti-tumor effects of OPN by silencing OPN expression in the gastric cancer cell line SGC7901, using lentiviral-OPN small interfering RNA (siRNA) technology. Plasmid vectors containing OPN siRNAs were generated, encoded with lentiviral vector and transfected into SGC7901 cells (SGC-OPN- cells). OPN mRNA and protein expression were examined using real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blotting techniques. The tumorigenicity and metastatic potential of SGC7901 cells were studied in nude mice. Expression of OPN and vascular endothelial growth factor (VEGF) in lung metastatic tumor specimens were also examined using immunohistochemistry (IHC). Among the three siRNA sequences tested, siRNA2 most remarkably inhibited mRNA levels of OPN; lentiviral-siRNA2 was stably transfected into SGC7901 cells to generate SGC-OPN- cells. SGC-OPN- cells had significantly decreased OPN expression compared to control cells (relative intensities were 0.14 ± 0.06 vs. 0.95 ± 0.16 in controls, P<0.01). A substantial reduction in detectable tumors was found in mice implanted with SGC-OPN- cells compared to controls (4.62 ± 1.24 vs. 8.35 ± 2.27 cm3 in controls, P<0.01). In addition, mice implanted with SGC-OPN- cells survived longer (101.2 ± 22.5 vs. 89.2 ± 24.6 d, P<0.01) and were demonstrated to have less metastases compared to mice implanted with SGC7901 control cells. Interestingly, lentiviral-siRNA2 also suppressed the expression of OPN and VEGF in metastatic lung specimens. Lentiviral-mediated OPN siRNA significantly reduced OPN gene expression, suppressing the growth and metastasis of gastric cancers, which might be related to reduced expression of VEGF. Therefore, OPN could serve as a promising therapeutic target for gastric cancer.

FoxO3a confers cetuximab resistance in RAS wild-type metastatic colorectal cancer through c-Myc

Resistance to epidermal growth factor receptor (EGFR) targeted monoclonal antibody therapy represents a clinical challenge in patients suffered from RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, the molecular mechanisms and key factors conferring this resistance are largely unknown. Forkhead transcription factors of the O class 3a (FoxO3a), an important regulator of cell survival, has been reported with dual functions in tumor recently. In this study, we found that FoxO3a was highly expressed in cetuximab resistant CRC tissues compared with cetuximab sensitive tissues. We therefore further analyzed its function in induced cetuximab resistant RAS-WT CRC cells (Caco2-CR) and intrinsic resistant cells with BRAF mutation (HT29). We found that FoxO3a was significantly up-regulated in Caco2-CR as well as in cetuximab treated HT29 cells. Knockdown of FoxO3a could sensitize these cells to cetuximab treatment with reduced cell proliferation and migration ability. Further, biochemical experiments demonstrated that FoxO3a directly bind to c-Myc promoter and activated the transcription of the c-Myc gene, thus participated in regulating of c-Myc downstream genes, including ACO2, LARS2, MRPL12 and PKM2 in these resistant cells. Moreover, knockdown of c-Myc elevated cell apoptosis to cetuximab treatment and suppressed cell proliferation and migration ability consistently. Altogether, our study indicates that FoxO3a might be a key regulator in cetuximab resistance through up-regulating c-Myc in colorectal cancer targeted therapy.

Asparaginyl endopeptidase promotes the invasion and metastasis of gastric cancer through modulating epithelial-to-mesenchymal transition

Asparaginyl endopeptidase (AEP) is a lysosomal protease often overexpressed in gastric cancer. AEP was expressed higher in peritoneal metastatic loci than in primary gastric cancer. Then we overexpressed AEP or knocked it down with a lentiviral vector in gastric cancer cell lines and detected the cell cycle arrest and the changes of the invasive and metastatic ability in vitro and in vivo. When AEP was knocked-down, the proliferative, invasive and metastatic capacity of gastric cancer cells were inhibited, and the population of sub-G1 cells increased. AEP knockdown led to significant decrease of expression of transcription factor Twist and the mesenchymal markers N-cadherin, ß-catenin and Vimentin and to increased expression of epithelial marker E-cadherin. These results showed that AEP could promote invasion and metastasis by modulating EMT. We used phosphorylation-specific antibody microarrays to investigate the mechanism how AEP promotes gastric cancer invasion and metastasis, and found that the phosphorylation level of AKT and MAPK signaling pathways was decreased significantly if AEP was knocked-down. Therefore, AKT and MAPK signaling pathways took part in the modulation.

Primary Tumour Resection Could Improve the Survival of Unresectable Metastatic Colorectal Cancer Patients Receiving Bevacizumab-Containing Chemotherapy

Background: The effect of primary tumour resection (PTR) among metastatic colorectal cancer (mCRC) patients remains controversial. Combination chemotherapy with bevacizumab could improve the clinical outcomes of these patients, which might change the importance of PTR in the multi-disciplinary treatment pattern. Methods: We performed a non-randomized prospective controlled study of mCRC pts whose performance status (PS) scored ≤2 and who received bevacizumab combination chemotherapy (FOLFOX/XELOX/FOLFIRI) as a first-line therapy. These patients were classified into the PTR group and the IPT (intact primary tumour) group according to whether they underwent PTR before receiving the systemic therapy. The progression free survival (PFS) time and overall survival (OS) time, which were recorded from the start of the primary diagnosis until disease progression and death or last follow-up, were analysed. We also compared severe clinical events (such as emergency surgery, radiation therapy, and stent plantation) between the two groups. Results: One hundred and nighty-one mCRC pts (108 male patients and 93 female patients) were entered in this prospective observational study. The median age was 57.5 years old. The clinical characteristics (age, gender, performance status, primary tumour site, RAS status, and the number of metastatic organs) did not significantly differ between the two groups. The median PFS and OS times of the PTR group were superior than those of the IPT group (10.0 vs 7.8 months, p < 0.01 and 22.5 vs 17.8 months, p < 0.01, respectively). The incidences of adverse events associated with systemic therapy were similar between the two groups. Specifically, sixteen patients (21.9%, 16/73) with IPT developed significant primary tumour-related complications, such as bleeding, obstruction or even perforation. Among these patients, five underwent emergency surgery, three patients received a stent, and eight patients underwent radiation therapy. Conclusions: The mCRC patients who received PTR and bevacizumab combination chemotherapy had better clinical outcomes than patients who did not receive PTR. PTR also decreased the incidence of severe clinical events and improved quality of life.

HSP27 expression levels are associated with the sensitivity of hepatocellular carcinoma cells to 17-allylamino-17-demethoxygeldanamycin

UNLABELLED AIMS, MATERIALS & METHODS: As heat-shock proteins are associated with tumor proliferation, differentiation, invasion and metastasis, we investigated whether targeting Hsp90 with the geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17AAG) can inhibit the viability of hepatocellular carcinoma cell lines with various levels of metastatic potential. In addition, we investigated whether the use of Hsp27-siRNA can decrease resistance to 17AAG. RESULTS Although 17AAG upregulated the expression of heat-shock proteins, it did not affect the expression of Hsp90 client proteins in normal hepatocytes. Hsp90 inhibition by 17AAG degraded its client proteins in both low- and high-metastatic potential cell lines. siRNA inhibited Hsp27 expression in cell lines and improved the sensitivity of 17AAG. CONCLUSION 17AAG inhibited the viability of hepatocellular carcinoma cells by degrading Hsp90 client proteins. The sensitivity of cells to 17AAG is associated with the level of Hsp27 expression.

Platelet-to-lymphocyte ratio and lymphocyte-to-white blood cell ratio predict the efficacy of neoadjuvant chemotherapy and the prognosis of locally advanced gastric cancer patients treated with the oxaliplatin and capecitabine regimen

Background Many studies have discussed the relationship between routine blood parameters and the prognosis of gastric cancer patients; however, few studies focused on the association of routine blood parameters with the efficacy of neoadjuvant chemotherapy (NAC). Patients and methods We retrospectively collected routine blood parameters and other clinicopathological data of 104 patients with locally advanced gastric cancer (LAGC) who received the oxaliplatin and capecitabine regimen as NAC from June 2010 to March 2016. The objective response rate (ORR), pathological remission rate (pRR), overall survival (OS), and time to recurrence (TTR) were analyzed through different statistical methods, such as Chi-squared test, log-rank test, logistic regression, and Cox regression. Results In the multivariate analysis, a high platelet-to-lymphocyte ratio (PLR) (≥130.7) predicted a low ORR (OR =5.927, 95% CI: 2.184–16.089) and a low pRR (OR =8.343, 95% CI: 2.178–31.962), while a high lymphocyte-to-white blood cell ratio (LWR) (≥0.228) independently predicted a high ORR (OR =0.118, 95% CI: 0.031–0.448) and a high pRR (OR =0.096, 95% CI: 0.021–0.426). High lymphocyte level (≥1.750×109/L) was an independent predictor of long OS (HR =0.428, 95% CI: 0.190–0.964) and long TTR (HR =0.328, 95% CI: 0.156–0.690). High monocyte level (≥0.215×109/L) was associated with a high pRR (OR =0.072, 95% CI: 0.008–0.636) and a long OS (HR = 0.506, 95% CI: 0.257–0.997). Conclusion In patients with LAGC treated with the oxaliplatin and capecitabine regimen as NAC, a low PLR (<130.7) and a high LWR (≥0.228) independently predicted a high ORR and pRR. High monocyte level (≥0.215×109/L) was an independent predictor for a high pRR and long OS, while patients with high lymphocyte level (≥1.750×109/L) tended to have a long OS and TTR.

An Analysis of Relationship Between RAS Mutations and Prognosis of Primary Tumour Resection for Metastatic Colorectal Cancer Patients

Background/Aims: Non-radical primary tumour resection (PTR) of asymptomatic metastatic colorectal cancer (mCRC) can prolong survival time of some patients. Patients with mutated RAS gene have worse survival outcome. This study aimed to investigate the impact of RAS gene mutations on the prognosis of asymptomatic unresectable mCRC patients who underwent PTR. Methods: A retrospective observational cohort study was deduced among mCRC patients who experienced PTR or had intact primary tumour (IPT). All of them had the primary tumour tissue genotyping tested for RAS (KRAS and NRAS) gene mutations. The tumour-related overall survival (OS) time and progression-free survival (PFS) time was estimated. From January 2011 to June 2014, 421 mCRC patients with asymptomatic, unresectable, metastatic disease were enrolled in this study. Among them, 282 patients underwent PTR and 139 patients had IPT. Results: The mutation rate of RAS was 53.8% (221/411). With a median followed-up time of 46.5 months, the overall survival time of mCRC patients harboring wtRAS or mtRAS was 28.0 versus 22.0 months (p = 0.043) in PTR group and was 21.6 versus 17.8 months (p=0.071) in IPT groups. A Multivariate regression analysis suggested that RAS gene (p=0.039, HR=1.288,95%CI [1.072∼2.911]), metastatic organ number (p=0.033, HR=3.091,95%CI [1.090∼5.755]) and systemic therapy response (p=0.019, HR=0.622,95%CI [0.525∼0.811]) were independent prognostic factors in PTR population. Conclusion: We found that wild-type RAS gene was a favorable factor for the asymptomatic unresectable mCRC patients experiencing PTR.