scholarly journals Colorectal cancer-associated fibroblasts promote metastasis by up-regulating LRG1 through stromal IL-6/STAT3 signaling

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Beiping Zhong ◽  
Bing Cheng ◽  
Xiaoming Huang ◽  
Qian Xiao ◽  
Zhitong Niu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Ex Vivo ◽  
Migration And Invasion ◽  
Clinical Samples ◽  
Specific Marker ◽  
Cancer Associated Fibroblasts ◽  
Primary Tumors ◽  
Mesenchymal Transition

AbstractCancer-associated fibroblasts (CAFs) have been shown to play a strong role in colorectal cancer metastasis, yet the underlying mechanism remains to be fully elucidated. Using CRC clinical samples together with ex vivo CAFs-CRC co-culture models, we found that CAFs induce expression of Leucine Rich Alpha-2-Glycoprotein 1(LRG1) in CRC, where it shows markedly higher expression in metastatic CRC tissues compared to primary tumors. We further show that CAFs-induced LRG1 promotes CRC migration and invasion that is concomitant with EMT (epithelial-mesenchymal transition) induction. In addition, this signaling axis has also been confirmed in the liver metastatic mouse model which displayed CAFs-induced LRG1 substantially accelerates metastasis. Mechanistically, we demonstrate that CAFs-secreted IL-6 (interleukin-6) is responsible for LRG1 up-regulation in CRC, which occurs through a direct transactivation by STAT3 following JAK2 activation. In clinical CRC tumor samples, LRG1 expression was positively correlated with CAFs-specific marker, α-SMA, and a higher LRG1 expression predicted poor clinical outcomes especially distant metastasis free survival, supporting the role of LRG1 in CRC progression. Collectively, this study provided a novel insight into CAFs-mediated metastasis in CRC and indicated that therapeutic targeting of CAFs-mediated IL-6-STAT3-LRG1 axis might be a potential strategy to mitigate metastasis in CRC.

scholarly journals SPNS2 Downregulation Induces EMT and Promotes Colorectal Cancer Metastasis via Activating AKT Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Lei Lv ◽  
Qiyi Yi ◽  
Ying Yan ◽  
Fengmei Chao ◽  
Ming Li
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Migration And Invasion ◽  
Akt Inhibitor ◽  
Colon Adenoma ◽  
Mesenchymal Transition

Spinster homologue 2 (SPNS2), a transporter of S1P (sphingosine-1-phosphate), has been reported to mediate immune response, vascular development, and pathologic processes of diseases such as cancer via S1P signaling pathways. However, its biological functions and expression profile in colorectal cancer (CRC) is elusive. In this study, we disclosed that SPNS2 expression, which was regulated by copy number variation and DNA methylation of its promoter, was dramatically upregulated in colon adenoma and CRC compared to normal tissues. However, its expression was lower in CRC than in colon adenoma, and low expression of SPN2 correlated with advanced T/M/N stage and poor prognosis in CRC. Ectopic expression of SPNS2 inhibited cell proliferation, migration, epithelial–mesenchymal transition (EMT), invasion, and metastasis in CRC cell lines, while silencing SPNS2 had the opposite effects. Meanwhile, measuring the intracellular and extracellular level of S1P after overexpression of SPNS2 pinpointed a S1P-independent model of SPNS2. Mechanically, SPNS2 led to PTEN upregulation and inactivation of Akt. Moreover, AKT inhibitor (MK2206) abrogated SPNS2 knockdown-induced promoting effects on the migration and invasion, while AKT activator (SC79) reversed the repression of migration and invasion by SPNS2 overexpression in CRC cells, confirming the pivotal role of AKT for SPNS2’s function. Collectively, our study demonstrated the suppressor role of SPNS2 during CRC metastasis, providing new insights into the pathology and molecular mechanisms of CRC progression.

scholarly journals Aldolase B Overexpression is Associated with Poor Prognosis and Promotes Tumor Progression by Epithelial-Mesenchymal Transition in Colorectal Adenocarcinoma

2017 ◽  
Vol 42 (1) ◽  
pp. 397-406 ◽  
Author(s):  
Qingguo Li ◽  
Yaqi Li ◽  
Junyan Xu ◽  
Sheng Wang ◽  
Ye Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Enzymatic Reaction ◽  
Disease Free Survival ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Aldolase B

Background: Glycolysis is considered to be the root of cancer development and progression, which involved a multi-step enzymatic reaction. Our study aimed at figuring out which glycolysis enzyme participates in the development of colorectal cancer and its possible mechanisms. Methods: We firstly screened out Aldolase B (ALDOB) by performing qRT-PCR arrays of glycolysis-related genes in five paired liver metastasis and primary colorectal tissues, and further detected ALDOB protein with immunohistochemistry in tissue microarray (TMA) consisting of 229 samples from stage I-III colorectal cancer patients. CRISPR-Cas9 method was adopted to create knock out colon cancer cell lines (LoVo and SW480) of ALDOB. The effect of ALDOB on cell proliferation and metastasis was examined in vitro using colony formation assay as well as transwell migration and invasion assay, respectively. Results: In TMA, there was 64.6% of samples demonstrated strong intensity of ALDOB. High ALDOB expression were associated with poor overall survival and disease-free survival in both univariate and multivariate regression analyses (P<0.05). In vitro functional studies of CCK-8 demonstrated that silencing ALDOB expression significantly (P<0.05) inhibited proliferation, migration and invasion of colon cancer cells. Mechanically, silencing ALDOB activated epithelial markers and repressed mesenchymal markers, indicating inactivation of ALDOB may lead to inhibition of epithelial-mesenchymal transition (EMT). Conclusion: Upregulation of ALDOB promotes colorectal cancer metastasis by facilitating EMT and acts as a potential prognostic factor and therapeutic target in colorectal cancer.

scholarly journals Comprehensive profiling of novel epithelial–mesenchymal transition mediators and their clinical significance in colorectal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Satoshi Ishikawa ◽  
Naohiro Nishida ◽  
Shiki Fujino ◽  
Takayuki Ogino ◽  
Hidekazu Takahashi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Gene Signature ◽  
Clinical Samples ◽  
Phenotypic Change ◽  
Mesenchymal Transition ◽  
Aggressive Cancer ◽  
Neuronal Gene ◽  
Functional Alteration

AbstractEpithelial–mesenchymal transition (EMT) is a drastic phenotypic change during cancer metastasis and is one of the most important hallmarks of aggressive cancer. Although the overexpression of some specific transcription factors explains the functional alteration of EMT-induced cells, a complete picture of this biological process is yet to be elucidated. To comprehensively profile EMT-related genes in colorectal cancer, we quantified the EMT induction ability of each gene according to its similarity to the cancer stromal gene signature and termed it “mesenchymal score.” This bioinformatic approach successfully identified 90 candidate EMT mediators, which are strongly predictive of survival in clinical samples. Among these candidates, we discovered that the neuronal gene ARC, possibly originating from the retrotransposon, unexpectedly plays a crucial role in EMT induction. Profiling of novel EMT mediators we demonstrated here may help understand the complexity of the EMT program and open up new avenues for therapeutic intervention in colorectal cancer.

scholarly journals SIRT1 promotes EMT, migration and invasion by regulating mTORC1/4E-BP1 in colorectal cancer

2020 ◽  
Author(s):  
Peifeng Liu ◽  
Xiaojing Chen ◽  
Shaolan Qin ◽  
Yan Zhou ◽  
Bo Yu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Tumors ◽  
Tumor Resection ◽  
Underlying Mechanism ◽  
Migration And Invasion ◽  
Mtor Inhibition ◽  
Primary Tumors ◽  
Mesenchymal Transition

Abstract Background Metastasis, rather than primary tumors, was accounted for the most cases of cancer death in colorectal cancer(CRC). The understanding of the underlying mechanism associated with tumor metastasis would improve the patient’s miserable fate. SIRT1 has been identified to play a role in tumorigenesis and progression of malignant tumors, especially in keeping the characteristics of cancer stem cells(CSCs) in CRC. This study was conducted to investigate the role of SIRT1 in the regulation of metastasis and the underlying mechanism in colorectal cancer. Methods We detected the expression of SIRT1 in 42 metastatic CRC patients. The relationship between SIRT1 and time to metastasis was also analyzed. Then the SIRT1 activity was regulated to investigate the liver metastasis in BALB/c mice. SIRT1 was knocked down to evaluate the effect on migration and invasion. Besides, exogenetic SIRT1 to assess the motile ability by wound healing assay and transwell assay. We then further explored the underlying mechanism. Results SIRT1 was overexpressed in 67% CRC metastatic patients and associated with reduced time to metastasis. High SIRT1 activity by resveratrol was companied with more liver metastasis in vivo. SIRT1 deficiency increased E-cadherin, while reduced Vimentin and Snail, attenuated migration and invasion significantly in CT26 and SW620 cells. Meanwhile, the exogenetic SIRT1 induced epithelial–mesenchymal transition (EMT) and elevated the migratory ability in SW480 cells. Further studies demonstrated that mTORC1 related genes were elevated while 4E-BP1 decayed by SIRT1 overexpression. The promotion of metastasis induced by SIRT1 overexpression could be abolished by mTOR inhibition, while the stemness of cells was not changed. Conclusions Collectively, our findings illustrated that SIRT1 was a functional regulator in the promotion of metastasis in CRC via mTORC1-4E-BP1 axis. SIRT1 was a potential independent prognostic factor of CRC metastatic patients after tumor resection, which provided a promising treatment target in CRC.

scholarly journals TdIF1-LSD1 Axis Regulates Epithelial—Mesenchymal Transition and Metastasis via Histone Demethylation of E-Cadherin Promoter in Lung Cancer

2021 ◽  
Vol 23 (1) ◽  
pp. 250
Author(s):  
Qi Liu ◽  
Juan Xiong ◽  
Derong Xu ◽  
Nan Hao ◽  
Yujuan Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Promoter Region ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Clinical Samples ◽  
Related Factors ◽  
Mesenchymal Transition ◽  
E Cadherin

We have previously found that TdT-interacting factor 1 (TdIF1) is a potential oncogene expressed in non-small cell lung cancer (NSCLC) and is associated with poor prognosis. However, its exact mechanism is still unclear. The lysine-specific demethylase 1 (LSD1) is a crucial mediator of the epithelial–mesenchymal transition (EMT), an important process triggered during cancer metastasis. Here, we confirm that TdIF1 is highly expressed in NSCLC and related to lymph node metastasis through The Cancer Genome Atlas (TCGA) analysis of clinical samples. Silencing TdIF1 can regulate the expression of EMT-related factors and impair the migration and invasion ability of cancer cells in vitro. An analysis of tumor xenografts in nude mice confirmed that silencing TdIF1 inhibits tumor growth. Furthermore, we determined the interaction between TdIF1 and LSD1 using immunoprecipitation. Chromatin immunoprecipitation (ChIP) revealed that TdIF1 was enriched in the E-cadherin promoter region. The knockdown of TdIF1 repressed the enrichment of LSD1 at the E-cadherin promoter region, thereby regulating the level of promoter histone methylation and modulating E-cadherin transcription activity, ultimately leading to changes in EMT factors and cancer cell migration and invasion ability. The LSD1 inhibitor and TdIF1 knockdown combination showed a synergistic effect in inhibiting the growth, migration, and invasion of NSCLC cells. Taken together, this is the first demonstration that TdIF1 regulates E-cadherin transcription by recruiting LSD1 to the promoter region, thereby promoting EMT and tumor metastasis and highlighting the potential of TdIF1 as a therapeutic target for NSCLC.

scholarly journals Proteomics and liquid biopsy characterization of human EMT-related metastasis in colorectal cancer

2021 ◽  
Author(s):  
Linhai Yan ◽  
Hai-Ming Ru ◽  
Si-Si Mo ◽  
Chun-Yin Wei ◽  
Dai-Mou Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Distant Metastases ◽  
Related Protein ◽  
Proteomics Data ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Data Independent Acquisition ◽  
Related Proteins

Abstract Introduction: Circulating tumor cells (CTCs) undergo epithelial-mesenchymal transition (EMT), and the heterogeneity of EMT possibly affects colorectal cancer metastasis (mCRC) evolution. The aim of this study was to identify novel metastasis-related proteins and EMT-related pathways.Methods: The EMT status of the CTCs derived from CRC patients with liver metastasis was determined on the basis of surface markers. Comparative proteomic analysis was then performed on matched pairs of primary tumors, adjacent para-tumor and liver metastases tissues. An optimized proteomic workflow including data independent acquisition (DIA) and parallel reaction monitoring (PRM) was used to screen for novel EMT-related protein clusters. Results: The proportion of the unstable epithelial/mesenchymal (E/M)-type CTCs correlated significantly with distant metastases. We screened 105 proteins related to EMT from 4,752 proteins identified in all samples, of which 40 proteins were differentially expressed across the different tissues. We identified a novel EMT-related protein cluster (e.g., GNG2, COL6A1, COL6A2, DCN, COL6A3, LAMB2, TNXB, CAVIN1) and found that the expression levels of the core EMT-related proteins KRAS and ERBB2 were altered during metastasis progression. The proteomics data indicated that KRAS, ERBB2, COL6A1 and CAVIN1 are promising EMT-related metastatic biomarkers.Conclusions: The plasticity of EMT phenotypes in the CTCs are key to CRC metastasis, prognosis and treatment outcome. Therapies targeting this aggressive CTC subset and the related proteins may suppress metastatic evolution.

scholarly journals Oxidized Phospholipids in Tumor Microenvironment Stimulate Tumor Metastasis via Regulation of Autophagy

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 558
Author(s):  
Jin Kyung Seok ◽  
Eun-Hee Hong ◽  
Gabsik Yang ◽  
Hye Eun Lee ◽  
Sin-Eun Kim ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Autophagic Flux ◽  
Oxidized Phospholipids ◽  
Mcf7 Cells ◽  
Mesenchymal Transition ◽  
Tumor Tissues

Oxidized phospholipids are well known to play physiological and pathological roles in regulating cellular homeostasis and disease progression. However, their role in cancer metastasis has not been entirely understood. In this study, effects of oxidized phosphatidylcholines such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) on epithelial-mesenchymal transition (EMT) and autophagy were determined in cancer cells by immunoblotting and confocal analysis. Metastasis was analyzed by a scratch wound assay and a transwell migration/invasion assay. The concentrations of POVPC and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine (PGPC) in tumor tissues obtained from patients were measured by LC-MS/MS analysis. POVPC induced EMT, resulting in increase of migration and invasion of human hepatocellular carcinoma cells (HepG2) and human breast cancer cells (MCF7). POVPC induced autophagic flux through AMPK-mTOR pathway. Pharmacological inhibition or siRNA knockdown of autophagy decreased migration and invasion of POVPC-treated HepG2 and MCF7 cells. POVPC and PGPC levels were greatly increased at stage II of patient-derived intrahepatic cholangiocarcinoma tissues. PGPC levels were higher in malignant breast tumor tissues than in adjacent nontumor tissues. The results show that oxidized phosphatidylcholines increase metastatic potential of cancer cells by promoting EMT, mediated through autophagy. These suggest the positive regulatory role of oxidized phospholipids accumulated in tumor microenvironment in the regulation of tumorigenesis and metastasis.

Galectin-3: A factotum in carcinogenesis bestowing an archery for prevention

Tumor Biology ◽  
2021 ◽  
Vol 43 (1) ◽  
pp. 77-96
Author(s):  
T. Jeethy Ram ◽  
Asha Lekshmi ◽  
Thara Somanathan ◽  
K. Sujathan
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Cellular Level ◽  
Clinical Samples ◽  
Innovative Strategy ◽  
Mesenchymal Transition ◽  
Galectin 3

Cancer metastasis and therapy resistance are the foremost hurdles in oncology at the moment. This review aims to pinpoint the functional aspects of a unique multifaceted glycosylated molecule in both intracellular and extracellular compartments of a cell namely galectin-3 along with its metastatic potential in different types of cancer. All materials reviewed here were collected through the search engines PubMed, Scopus, and Google scholar. Among the 15 galectins identified, the chimeric gal-3 plays an indispensable role in the differentiation, transformation, and multi-step process of tumor metastasis. It has been implicated in the molecular mechanisms that allow the cancer cells to survive in the intravascular milieu and promote tumor cell extravasation, ultimately leading to metastasis. Gal-3 has also been found to have a pivotal role in immune surveillance and pro-angiogenesis and several studies have pointed out the importance of gal-3 in establishing a resistant phenotype, particularly through the epithelial-mesenchymal transition process. Additionally, some recent findings suggest the use of gal-3 inhibitors in overcoming therapeutic resistance. All these reports suggest that the deregulation of these specific lectins at the cellular level could inhibit cancer progression and metastasis. A more systematic study of glycosylation in clinical samples along with the development of selective gal-3 antagonists inhibiting the activity of these molecules at the cellular level offers an innovative strategy for primary cancer prevention.

scholarly journals Upregulation of FBXW7 Suppresses Renal Cancer Metastasis and Epithelial Mesenchymal Transition

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Yangke Cai ◽  
Meng Zhang ◽  
Xiaofu Qiu ◽  
Bingwei Wang ◽  
Yu Fu ◽  
...  
Keyword(s):  
Cell Lines ◽  
Renal Cell ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Coding Region ◽  
Mesenchymal Transition ◽  
Renal Cell Line ◽  
Emt Markers

Background and Objective. FBXW7, known as a general tumor suppressor, is commonly lowly expressed in metastatic malignancies. We aim to investigate the potential influence of FBXW7 overexpression on renal cell carcinoma (RCC) metastasis. Methods. We employed quantitative real-time PCR (qRT-PCR) and Western blotting (WB) to quantify the FBXW7 expression in RCC cell lines. Upregulation of FBXW7 was performed in vitro on RCC cells using the lentivirus covering coding region FBXW7 cDNA sequence, and functional tests were performed to verify FBXW7 overexpression on migration and invasion of RCC cells. Moreover, WB was employed to determine the expressions of MMP-2, MMP-9, and MMP-13, as well as EMT markers in the transfected RCC cells. Results. FBXW7 was significantly downregulated in RCC cell lines, dominated by 786-O and ACHN, when compared to normal renal cell line HK-2. Moreover, upregulation of FBXW7 in 786-O and ACHN cell lines significantly inhibited cell migration and invasion, as well as EMT. Present study also showed that FBXW7 was involved in the migration and invasion of RCC cells via regulating the expressions of MMP-2, MMP-9, and MMP-13. Conclusion. Our findings demonstrate that upregulation of FBXW7 inhibits RCC metastasis and EMT. FBXW7 is a potential therapeutic target for RCC patients.

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