Inverse association between Bmi-1 and RKIP affecting clinical outcome of gastric cancer and revealing the potential molecular mechanisms underlying tumor metastasis and chemotherapy resistance

Chen, Yinting; Lian, Guoda; Ou, Guangsheng; Yang, Kege; Chen, Jianning; Li, Haigang; Chen, Shaojie; Li, Jiajia; Zeng, Linjuan; Huang, Kaihong

doi:10.1007/s10120-015-0485-0

Cited by 16 publications

(13 citation statements)

References 30 publications

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“…The association between Bmi-1, RKIP and the clinical outcome of gastric cancer has been reported in our previous study [10]. To further explore the clinical significance of Bmi-1, miR-27a, miR-155 and RKIP in GC, we first analyzed their RNA expression levels by qRT-PCR.…”

Section: Resultsmentioning

confidence: 91%

“…Furthermore, we demonstrated that Bmi-1 is inversely associated with Raf kinase inhibitory protein (RKIP), a regulator of apoptosis induced by chemotherapeutic agents and a clinically relevant cancer metastasis suppressor gene [8,9]. Based on previously reported results, the negative correlation between Bmi-1 and RKIP was deemed valuable in predicting patient survival and therapeutic response in GC [10]. The inverse expression pattern of Bmi-1 and RKIP was confirmed in GC cell lines by utilizing in vitro gene overexpression and silencing methods, suggesting the likelihood of RKIP being regulated by Bmi-1.…”

Section: Introductionmentioning

confidence: 74%

“…RKIP is a proven metastasis suppressor protein in various human cancer types and is linked to an invasive phenotype [24,25]. Low levels or the absence of RKIP expression in GC is associated with poor patient prognosis [10,26]. However, the molecular mechanisms of how RKIP expression is downregulated in GC remain unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Plasmids, siRNAs and stable cell lines pLNCX2-Bmi-1 was constructed as previously described [7]. Stable cells overexpressing Bmi-1, SGC7901-Bmi-1, BGC823-Bmi-1, GES-1-Bmi-1#1 and GES-1-Bmi-1#2 were generated by retroviral transfection as described in our previous study [7,10]. The Bmi-1 overexpressing cells were also named Vector-Bmi-1, and the negative control was named Vector-Ctrl.…”

Section: Cell Linesmentioning

confidence: 99%

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Bmi-1-induced miR-27a and miR-155 promote tumor metastasis and chemoresistance by targeting RKIP in gastric cancer

Tian

Tan

et al. 2020

Mol Cancer

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Background: We previously reported an inverse relationship between B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and Raf kinase inhibitory protein (RKIP), which is associated with the prognosis of gastric cancer (GC). In this study, we further explored the microRNA (miRNA) regulatory mechanism between Bmi-1 and RKIP. Methods: Microarray analysis was first carried out to identify miRNA profiles that were differentially expressed in cells overexpressing Bmi-1. Then, miRNAs that could regulate RKIP were identified. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to measure the expression of Bmi-1, miR-155, miR-27a and RKIP. RKIP was confirmed as a target of miR-27a and miR-155 through luciferase reporter assays, qRT-PCR and Western blotting. The effects of the Bmi-1/miR-27a/RKIP and Bmi-1/miR-155/RKIP axes on tumor growth, proliferation, migration, invasion, colony-formation ability, metastasis and chemoresistance were investigated both in vitro and in vivo. Results: The downregulation of RKIP by Bmi-1 occurred at the protein but not mRNA level. This indicates probable posttranscriptional regulation. miRNA expression profiles of cells with ectopic expression of Bmi-1 were analyzed and compared to those of control cells by microarray analysis. A total of 51 upregulated and 72 downregulated miRNAs were identified. Based on publicly available algorithms, miR-27a and miR-155 were predicted, selected and demonstrated to target RKIP. Bmi-1, miR-27a and miR-155 are elevated in human GC and associated with poor prognosis of GC, while RKIP is expressed at lower levels in GC and correlated with good prognosis. Then, in vitro tests shown that in addition to regulating RKIP expression via miR-27a and miR-155, Bmi-1 was also able to regulate the migration, invasion, proliferation, colony-formation ability and chemosensitivity of GC cells through the same pathway. Finally, the in vivo test showed similar results, whereby the knockdown of the Bmi-1 gene led to the inhibition of tumor growth, metastasis and chemoresistance through miR-27a and miR-155.

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Section: Resultsmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Cell Linesmentioning

confidence: 99%

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Bmi-1-induced miR-27a and miR-155 promote tumor metastasis and chemoresistance by targeting RKIP in gastric cancer

Tian

Tan

et al. 2020

Mol Cancer

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“…Pair-matched tumorous and adjacent nontumorous gastric tissues from 33 patients undergoing resection for gastric cancer were obtained from Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University (Guangzhou, China). Tissue microarray (TMA) containing 107 gastric cancer tumor tissue constructed as described in our previous study [24]. The study was carried out in accordance with the…”

Section: Human Tissue Samples and Cell Linesmentioning

confidence: 99%

miR-543 inhibits tumor malignant progression by regulating TWIST1 in human gastric cancer

Lian¹,

Li²,

Chen³

et al. 2020

Preprint

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Background: TWIST1, a highly conserved basic helix-loop-helix (bHLH) transcription factor, is essential to epithelial-mesenchymal transition (EMT) and cancer metastasis in gastric cancer (GC). However, little is known about the post-transcriptional regulation of TWIST1, especially the mechanisms involving microRNAs. Methods: TWIST1 expression were observed on 107 cases of gastric cancer through tissue microarray technology to identify their correlations with clinicopathological parameters and patient survival. The regulation of TWIST1 by miR-543 was confirmed by western blot, dual luciferase activity assays and rescue experiments. Moreover, the functions of miR-543 on cell migration, invasion, tumorigenicity and metastatic potential were evaluated by stably expression strategy in vitro and in vivo. Results: TWIST1 is overexpressed in 74 of 107 GC tumor samples. High TWIST1 expression positively correlated with poor prognosis of GC patients. In addition, TWIST1 was found to be a direct target of miR-543. Expression of miR-543 was obviously decreased in GC cell lines and primary tissues. Overexpression of miR-543 in GC cells inhibited proliferation, colony formation, migration and invasion by suppressing expression of TWIST1. Ectopic expression of miR-543 inhibited tumor growth and prevented liver metastasis of gastric cancer cells in mice. Conclusion: TWIST1 is overexpressed in gastric cancer and regulated by miR-543. Downregulated miR-543 promotes tumor growth and metastasis of GC, indicating the possibility of new strategies for GC therapy.

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Tumor‐driven like macrophages induced by conditioned media from pancreatic ductal adenocarcinoma promote tumor metastasis via secreting IL‐8

Chen

Lian

et al. 2018

Cancer Medicine

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Tumor‐associated macrophages (TAMs) are abundant population of inflammatory cells which play an essential role in remodeling tumor microenvironment and tumor progression. Previously, we found the high density of TAMs was correlated with lymph node metastasis and poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Therefore, this study was designed to investigate the mechanisms of interaction between TAMs and PDAC. THP‐1 monocytes were the exposure to conditioned media (CM) produced by PDAC cells; then, monocyte recruitment and macrophage differentiation were assessed. CM from PDAC attracted and polarized THP‐1 monocytes to tumor‐driven like macrophages. mRNA expression cytokine profiling and ELISA identified the IL‐8 secretion was increasing in tumor‐driven like macrophages, and STAT3 pathway was involved. Addition of exogenous recombinant human IL‐8 promoted PDAC cells motility in vitro and metastasis in vivo via upregulating Twist expression, which mediated epithelial‐mesenchymal transition in cancer cells. What is more, IL‐8 expression level in tumor stroma by immunohistochemical analysis was related to lymph node metastasis, the number of tumor CD68 but not CD163 positive macrophages and patient outcome. Taken together, these findings shed light on the important interplay between cancer cells and TAMs in tumor microenvironment and suggested that IL‐8 signaling might be a potential therapeutic target for PDAC.

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Inverse association between Bmi-1 and RKIP affecting clinical outcome of gastric cancer and revealing the potential molecular mechanisms underlying tumor metastasis and chemotherapy resistance

Cited by 16 publications

References 30 publications

Bmi-1-induced miR-27a and miR-155 promote tumor metastasis and chemoresistance by targeting RKIP in gastric cancer

Bmi-1-induced miR-27a and miR-155 promote tumor metastasis and chemoresistance by targeting RKIP in gastric cancer

miR-543 inhibits tumor malignant progression by regulating TWIST1 in human gastric cancer

Tumor‐driven like macrophages induced by conditioned media from pancreatic ductal adenocarcinoma promote tumor metastasis via secreting IL‐8

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