Qianshan Ding

Activated ERM Protein Plays a Critical Role in Drug Resistance of MOLT4 Cells Induced by CCL25

We have previously demonstrated that the CCR9/CCL25 signaling pathway plays an important role in drug resistance in human acute T-lymphocytic leukemia (T-ALL) by inducing activation of ERM protein with polarized distribution in T-ALL cell line MOLT4. However, the mechanism of action of the activated ERM protein in the drug resistance of MOLT4 cells induced by CCL25 remains uncharacterized. Here we investigated the mechanism of CCR9/CCL25-initiated drug resistance in CCR9-high-expressing T-ALL cells. Our results showed that 1) the function of P-gp was increased after treatment with CCL25; 2) P-gp colocalized and co-immunoprecipitated with p-ERM and F-actin in CCL25 treated cells; and 3) ERM-shRNA conferred drug sensitivity coincident with release of ERM interactions with P-gp and F-actin after treatment with CCL25. These data suggest it is pivotal that P-gp associate with the F-actin cytoskeleton through p-ERM in CCR9/CCL25 induced multidrug resistance of T-ALL cells. Strategies aimed at inhibiting P-gp-F-actin cytoskeleton association may be helpful in increasing the efficiency of therapies in T-ALL.

Activation of β-catenin signaling is critical for doxorubicin-induced epithelial-mesenchymal transition in BGC-823 gastric cancer cell line.

The epithelial–mesenchymal transition (EMT) is a fundamental process governing morphogenesis in multicellular organisms and has recently been implicated in promoting carcinoma invasion and metastasis. Besides their therapeutic effects, accumulating evidences suggest that chemotherapeutic agents also induced EMT and enhanced the malignancy of treated cancer cells; however, the mechanism(s) still remains unclear. Here, we investigated the role of β-catenin signaling in doxorubicin (Dox)-induced EMT in human gastric cancer cell line BGC-823. We found that the transient treatment of Dox induced EMT and enhanced the in vitro migration ability of cancer cells. We also found that β-catenin signaling was activated upon Dox treatment. Inhibition of β-catenin by indomethacin (Indo) or siRNA suppressed Dox-induced EMT and decreased cancer cell migration ability. Our results showed that β-catenin signaling was critical to Dox-induced EMT. Indo and other β-catenin inhibitors may have a potential implication in prevention of gastric cancer metastasis.

The direct effect of estrogen on cell viability and apoptosis in human gastric cancer cells.

Epidemiology researches indicated that gastric cancer is a male-predominant disease; both expression level of estrogen and expression pattern of estrogen receptors (ERs) influence its carcinogenesis. But the direct effect of estrogen on gastric cancer cells is still unclear. This study aimed to explore the direct effect of β-estradiol (E2) on gastric cancer cells. SGC7901 and BGC823 were treated with a serial of concentrations of E2. The survival rates of both the cell lines were significantly reduced, and the reduction of viability was due to apoptosis triggered by E2 treatment. Caspase 3 was activated in response to the increasing E2 concentration in both SGC7901 and BGC823. Cleaved Caspase 3 fragments were detected, and the expression levels of Bcl-2 and Bcl-xL were reduced. Apoptosis was further confirmed by flow cytometry. The expression level of PEG10, an androgen receptor target gene, was reduced during E2 treatment. Both ERα and ERβ were expressed in these cell lines, and the result of bioinformatics analysis of gastric cancer from GEO datasets indicated that the expression levels of both ERα and ERβ were significantly higher in noncancerous gastric tissues than in gastric cancer tissues. Our research indicated that estrogen can reduce cell viability and promote apoptosis in gastric cancer cells directly; ERs expression level is associated with gastric cancer. Our research will help to understand the mechanism of gender disparity in gastric cancer.

Downregulation of TRIM21 contributes to hepatocellular carcinoma carcinogenesis and indicates poor prognosis of cancers

The aim of our work is to clarify the clinical implication and functional role of tripartite motif 21 (TRIM21) in hepatocellular carcinoma (HCC). We validated that TRIM21 was downregulated in liver cancer samples by immunohistochemical (IHC) staining. We also demonstrated that its downregulation was associated with several clinicopathologic features such as tumor numbers, T stage, Barcelona Clinic Liver Cancer (BCLC) stage, and Cancer of the Liver Italian Program (CLIP) stage of HCC patients. Importantly, the expression of TRIM21 in tumor samples is significantly correlated with the prognosis of the patients. We further silenced TRIM21 in HCC cell HepG2 and LM3 and confirmed that TRIM21 silencing will promote cancer cell proliferation (CCK-8 assay), colony forming (plate colony-forming assay), migration (transwell assay), and the ability of antiapoptosis (annexin V-FITC/PI staining) in vitro. Then, we predicted gene sets influenced by TRIM21 by using bioinformatic tools. For the first time, we prove that TRIM21 is a potential tumor suppressor in HCC and its low expression indicates poor prognosis. Our findings provide useful insight into the mechanism of HCC origin and progression and offer clues to novel HCC therapies.

Aberrant high expression level of MORC2 is a common character in multiple cancers

Microrchidia 2 (MORC2) plays important roles in DNA damage repair and lipogenesis, but the clinical and functional role of MORC2 in cancer remains largely unexplored. In this study, we showed that MORC2 was widely expressed in human tissues while significantly up-regulated in most cancer types using immunohistochemical staining and analysis of messenger RNA expression profile of more than 2000 human tissue samples from 15 different organs (lung, prostate, liver, breast, brain, stomach, colon/rectum, pancreas, ovary, endometrium, skin, nasopharynx, kidney, esophagus, and bladder). We also found that the MORC2 expression level in high-grade cancer tissues was much more elevated and associated with unfavorable pathological characteristics, poor overall survival, and disease-free survival in several kinds of cancers such as non-small cell lung cancer and breast cancer. Gene set enrichment analysis was used to predict the genes modulated by MORC2, and the results showed that dysregulation of MORC2 in tumor may take part in the cell cycle regulation and genomic instability. We observed that MORC2 knockdown would arrest the cell cycle progress, and the genome of tumors with high MORC2 expression contained more point mutations and gene copy number variation, which validates our gene set enrichment analysis results. The results also showed that MORC2 knockdown would significantly inhibit the proliferation, colony forming, migration, and invasion in multiple cancer cell lines. Taken together, these results highlight the importance of MORC2 in tumorigenesis and cancer progression, and it may act as a potential diagnostic marker and therapeutic target for these diseases.

AGXT2L1 is down-regulated in heptocellular carcinoma and associated with abnormal lipogenesis

Aims To clarify the clinical implications and functional role of the alanine-glyoxylate aminotransferase 2-like 1 (AGXT2L1) gene in hepatocellular carcinoma (HCC). Methods and results We confirmed that AGXT2L1 was down-regulated in liver cancer samples by immunohistochemical (IHC) staining. We also demonstrated that this down-regulation was associated with several clinicopathological features such as alpha fetoprotein (AFP) serum level and T stage. Furthermore, we showed with Kaplan-Meier analysis that expression of AGXT2L1 in tumour samples was significantly correlated with patient prognosis. The bioinformatic tool indicated that AGXT2L1 plays a role in the lipid metabolic process of HCC tissue, while siRNA silenced the expression of AGXT2L1 in HCC 97H and LM3 cells, confirming that down-regulation of AGXT2L1 promotes the lipogenesis of cancer cells. Conclusions For the first time, we have shown that AGXT2L1 is down-regulated in HCC and its low expression indicates a poor prognosis. Our findings also demonstrated that AGXT2L1 is a crucial gene in the abnormal lipogenesis of HCC tissue.

MORC2, a novel oncogene, is upregulated in liver cancer and contributes to proliferation, metastasis and chemoresistance

Microrchidia 2 (MORC2) is important in DNA damage repair and lipogenesis, however, the clinical and functional role of MORC2 in liver cancer remains to be fully elucidated. The aim the present study was to clarify the role of MORC2 in liver cancer. Expression profile analysis, immunohistochemical staining, reverse transcription-quantitative polymerase chain reaction analysis and western blot analysis were performed to evaluate the levels of MORC2 in liver cancer patient specimens and cell lines; subsequently the expression of MORC2 was suppressed or increased in liver cancer cells and the effects of MORC2 on the cancerous transformation of liver cancer cells were examined in vitro and in vivo. MORC2 was upregulated in liver cancer tissues, and the upregulation was associated with certain clinicopathologic features of patients with liver cancer. MORC2 knockdown caused marked inhibition of liver cancer cell proliferation and clonogenicity, whereas the overexpression of MORC2 substantially promoted liver cancer cell proliferation. In addition, the knockdown of MORC2 inhibited the migratory and invasive ability of liver cancer cells, whereas increased migration and invasion rates were observed in cells with ectopic expression of MORC2. In a model of nude mice, the overexpression of MORC2 promoted tumorigenicity and markedly enhanced pulmonary metastasis of liver cancer. Furthermore, MORC2 regulated apoptosis and its expression level had an effect on the sensitivity of liver cancer cells to doxorubicin, 5-fluorouracil and cisplatin. Mechanically, MORC2 modulated the mitochondrial apoptotic pathway, possibly in a p53-dependent manner, and its dysregulation also resulted in the abnormal activation of the Hippo pathway. For the first time, to the best of our knowledge, the present study confirmed that MORC2 was a novel oncogene in liver cancer. These results provide useful insight into the mechanism underlying the tumorigenesis and progression of liver cancer, and offers clues into potential novel liver cancer therapies.

Assessment of micro-optical coherence tomography (μOCT) as an imaging tool for pancreatic disease diagnosis

As an emerging technique capable of providing cellular/subcellular-level tissue microstructure images, optical coherence tomography (OCT) is regarded to be a viable tool for early disease diagnosis, yet few studies on pancreatic imaging have ever been reported in literature. In this paper, we utilized a lab-built micro-OCT (μOCT) for cellular/subcellular pancreatic imaging for both normal tissues and those specimens with edema, and evaluate the feasibility of OCT as an imaging tool for early pancreatic disease diagnosis. Results show that the cellular/subcellular-level pancreatic microstructures of normal tissues could be clearly identified, and is quite different from those in tissues with edema. Such results demonstrate the great potential of μOCT as a viable tool for pancreatic tissue imaging in clinical practice.

Continued use of low-dose aspirin may increase risk of bleeding after gastrointestinal endoscopic submucosal dissection: A meta-analysis

BACKGROUND/AIMS Endoscopic submucosal dissection has been widely accepted. At present, the number of antiplatelet (APT) users has been growing. Moreover, because of high risks of thromboembolism, some patients need to continuously receive APT agents. The relationship between hemorrhage and continuous therapy with low-dose aspirin (LDA) remains controversial. MATERIALS AND METHODS A systematic search was conducted; studies were screened out- if data of no-anticoagulant/APT drugs use and interrupted and continued-LDA use were reported separately. The Newcastle-scale was chosen to assess the quality of the included studies. Review Manager 5.2 was used for quality assessment statistical analysis, and the odd ratio (OR) and 95% confidence interval (CI) were calculated. RESULTS Pooled data suggested a significantly higher bleeding ratio in the LDA-continued group compared to both the LDA-interrupted group (OR=2.05, 95% CI=1.05-3.99) and no-anticoagulant/APT group (OR=2.89, 95% CI=1.86-4.47). However, the LDA-interrupted group did not differ significantly from the no-anticoagulant/APT group. The en bloc resection rates of the LDA-continued group versus the LDA-interrupted group, the LDA-continued group versus no-anticoagulant/APT group, and the LDA-interrupted group versus the no-anticoagulant/APT group were similar (OR=0.82, 95% CI=0.21-3.24, p=0.78; OR=0.80, 95% CI=0.24-2.65, p=0.71; OR=1.41, 95% CI=0.38-5.24, p=0.60, respectively). CONCLUSION There is an extremely high ratio of bleeding in the LDA-continued group compared to both the LDA-interrupted group and no-anticoagulant/APT group. All groups had similar ratios of en bloc resection.

SSRP1 silencing inhibits the proliferation and malignancy of human glioma cells via the MAPK signaling pathway.

Structure-specific recognition protein 1 (SSRP1) has been considered as a potential biomarker, since aberrant high expression of SSRP1 has been detected in numerous malignant tumors. However, the correlation between the expression level of SSRP1 and glioma remains unclear. The present study attempted to investigate the role of SSRP1 in the pathogenesis of glioma. In the present study, our data revealed that SSRP1 overexpression was detected in glioma tissues at both the mRNA and protein levels using quantitative real-time RT-PCR and immunohistochemical analysis. We also demonstrated that the upregulated expression of SSRP1 was correlated with the World Health Organization (WHO) grade of glioma. The knockdown of SSRP1 by siRNA not only resulted in the inhibition of cell proliferation, but also significantly inhibited glioma cell migration and invasion. Mechanistic analyses revealed that SSRP1 depletion suppressed the activity of the phosphorylation of the MAPK signaling pathway. In conclusion, the present study indicated that SSRP1 regulated the proliferation and metastasis of glioma cells via the MAPK signaling pathway.