Loss of FBP1 by aPKC-ι/Snail Pathway-Mediated Repression Promotes Invasion and Aerobic Glycolysis of Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is one of the most commonly diagnosed malignancies worldwide, and the second most common primary liver tumor. The lack of effective diagnostic and treatment methods results in poor patient prognosis and high mortality rate. Atypical protein kinase C-ι (aPKC-ι) is highly expressed in primary and metastatic ICC tissues, and regulates epithelial mesenchymal transition (EMT) through the aPKC-ι/P-Sp1/Snail signaling pathway. Recent studies have correlated aberrant glucose metabolism with EMT. Given the vital role of FBP1 in regulating glucose metabolism in cancer cells, we hypothesized that aPKC-ι downregulates FBP1 in ICC cells through the Snai1 pathway, and enhances glycolysis and metastasis. We confirmed the ability of aPKC-ι promotes glycolysis, invasion and metastasis of cancer cells, and further demonstrated that FBP1 inhibits the malignant properties of ICC cells by antagonizing aPKC-ι. Our findings provide novel insights into the molecular mechanisms of ICC progression and metastasis, as well as a theoretical basis for exploring new treatment strategies.

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Functional antagonism of chromatin modulators regulates epithelial-mesenchymal transition

Science Advances ◽

10.1126/sciadv.abd7974 ◽

2021 ◽

Vol 7 (9) ◽

pp. eabd7974

Author(s):

Michela Serresi ◽

Sonia Kertalli ◽

Lifei Li ◽

Matthias Jürgen Schmitt ◽

Yuliia Dramaretska ◽

...

Keyword(s):

Cancer Cells ◽

Transcriptional Control ◽

Molecular Mechanisms ◽

Developmental Process ◽

Epithelial Mesenchymal Transition ◽

Chromatin Remodelers ◽

Mesenchymal Transition ◽

Signature Genes ◽

Chromatin Regulators ◽

The Impact

Epithelial-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to modulate proliferation, migration, and stress response. Whereas kinase signaling is believed to be an EMT driver, the molecular mechanisms underlying epithelial-mesenchymal interconversion are incompletely understood. Here, we show that the impact of chromatin regulators on EMT interconversion is broader than that of kinases. By combining pharmacological modulation of EMT, synthetic genetic tracing, and CRISPR interference screens, we uncovered a minority of kinases and several chromatin remodelers, writers, and readers governing homeostatic EMT in lung cancer cells. Loss of ARID1A, DOT1L, BRD2, and ZMYND8 had nondeterministic and sometimes opposite consequences on epithelial-mesenchymal interconversion. Together with RNAPII and AP-1, these antagonistic gatekeepers control chromatin of active enhancers, including pan-cancer-EMT signature genes enabling supraclassification of anatomically diverse tumors. Thus, our data uncover general principles underlying transcriptional control of cancer cell plasticity and offer a platform to systematically explore chromatin regulators in tumor-state–specific therapy.

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Dihydropyrimidinase Like 2 Promotes Bladder Cancer Progression via Pyruvate Kinase M2-Induced Aerobic Glycolysis and Epithelial–Mesenchymal Transition

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.641432 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jun Zou ◽

Ruiyan Huang ◽

Yanfei Chen ◽

Xiaoping Huang ◽

Huajun Li ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Pyruvate Kinase ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Aerobic Glycolysis ◽

Mesenchymal Transition ◽

Bladder Cancer Cells ◽

Malignant Behavior

BackgroundAerobic glycolysis and epidermal–mesenchymal transition (EMT) play key roles in the development of bladder cancer. This study aimed to investigate the function and the underlying mechanism of dihydropyrimidinase like 2 (DPYSL2) in bladder cancer progression.MethodsThe expression pattern of DPYSL2 in bladder cancer and the correlation of DPYSL2 expression with clinicopathological characteristics of bladder cancer patients were analyzed using the data from different databases and tissue microarray. Gain- and loss-of-function assays were performed to explore the role of DPYSL2 in bladder cancer progression in vitro and in mice. Proteomic analysis was performed to identify the interacting partner of DPYSL2 in bladder cancer cells.FindingsThe results showed that DPYSL2 expression was upregulated in bladder cancer tissue compared with adjacent normal bladder tissue and in more aggressive cancer stages compared with lower stages. DPYSL2 promoted malignant behavior of bladder cancer cells in vitro, as well as tumor growth and distant metastasis in mice. Mechanistically, DPYSL2 interacted with pyruvate kinase M2 (PKM2) and promoted the conversion of PKM2 tetramers to PKM2 dimers. Knockdown of PKM2 completely blocked DPYSL2-induced enhancement of the malignant behavior, glucose uptake, lactic acid production, and epithelial–mesenchymal transition in bladder cancer cells.InterpretationIn conclusion, the results suggest that DPYSL2 promotes aerobic glycolysis and EMT in bladder cancer via PKM2, serving as a potential therapeutic target for bladder cancer treatment.

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SQSTM1/p62 in Intrahepatic Cholangiocarcinoma Promotes Tumor Progression Via Epithelial-Mesenchymal Transition and Mitochondrial Function Maintenance

10.21203/rs.3.rs-964992/v1 ◽

2021 ◽

Author(s):

Jiafeng Chen ◽

Zheng Gao ◽

Xiaogang Li ◽

Yinghong Shi ◽

Zheng Tang ◽

...

Keyword(s):

Intrahepatic Cholangiocarcinoma ◽

Mitochondrial Function ◽

Epithelial Mesenchymal Transition ◽

Immunohistochemical Analysis ◽

Vital Role ◽

Loss Of Function ◽

Mesenchymal Transition ◽

Consumption Rates ◽

Invasive Capacity

Abstract Background: SQSTM1/p62, as a selective autophagy receptor, regulates multiple signaling pathways participating in the initiation and progression of tumors. Since metastasis is still a main cause for intrahepatic cholangiocarcinoma (ICC)-associated mortality, this study aimed to explore the mechanism of p62 promoting progression of ICC.Methods: Western blotting and immunohistochemical analysis were conducted to detect the expression level of protein p62 in ICC tissues. Subsequently, loss of function experiments was applied to define the role of p62 in the progression of ICC in vitro and in vivo. Mitochondrial function and mitophagy was evaluated by measuring oxygen consumption rates (OCR) and immunofluorescence detection respectively.Results: Here we identified expression of p62 was significantly upregulated in ICC specimens compared to normal tissue. And we further illustrated that p62 expression was positively correlated with lymph-node metastasis and poor prognosis. Loss of function assays revealed that p62 not only promoted ICC cells proliferation, migration and invasive capacity in vitro, but also induced lung metastasis in xenograft mouse model. Mechanistically, high expression of p62 induced epithelial-mesenchymal transition (EMT) with upregulation of Snail1, Vimentin and down-regulation of E-Cadherin. Moreover, OCR assays and immunofluorescence cell staining demonstrated that the autophagy-dependent function of p62 may play a vital role in maintaining mitochondrial function of ICC by mitophagy.Conclusions: These data provide new evidence and feasible mechanism that abundant p62 expression promote ICC progression, suggesting a promising therapeutic target for anti-metastatic strategies in ICC patients.

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The epithelial-mesenchymal transcription factor SNAI1 represses transcription of the tumor suppressor miRNA let-7 in cancer

10.1101/2020.11.04.368688 ◽

2020 ◽

Author(s):

H Wang ◽

E Chirshev ◽

N Hojo ◽

T Suzuki ◽

A Bertucci ◽

...

Keyword(s):

Ovarian Cancer ◽

Transcription Factor ◽

Stem Cell ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Tumor Burden ◽

Cell Phenotype ◽

Mesenchymal Transition

AbstractWe aimed to determine the mechanism of epithelial-mesenchymal transition (EMT)-induced stemness in cancer cells. Cancer relapse and metastasis are caused by rare stem-like cells within tumors. Studies of stem cell reprogramming have linked let-7 repression and acquisition of stemness with the EMT factor, SNAI1. The mechanisms for the loss of let-7 in cancer cells are incompletely understood. In four carcinoma cell lines from breast cancer, pancreatic cancer and ovarian cancer and in ovarian cancer patient-derived cells, we analyzed stem cell phenotype and tumor growth via mRNA, miRNA, and protein expression, spheroid formation, and growth in patient-derived xenografts. We show that treatment with EMT-promoting growth factors or SNAI1 overexpression increased stemness and reduced let-7 expression, while SNAI1 knockdown reduced stemness and restored let-7 expression. Rescue experiments demonstrate that the pro-stemness effects of SNAI1 are mediated via let-7. In vivo, nanoparticle-delivered siRNA successfully knocked down SNAI1 in orthotopic patient-derived xenografts, accompanied by reduced stemness and increased let-7 expression, and reduced tumor burden. Chromatin immunoprecipitation demonstrated that SNAI1 binds the promoters of various let-7 family members, and luciferase assays revealed that SNAI1 represses let-7 transcription. In conclusion, the SNAI1/let-7 axis is an important component of stemness pathways in cancer cells, and this study provides a rationale for future work examining this axis as a potential target for cancer stem cell-specific therapies.Novelty and ImpactThis study provides new insight into molecular mechanisms by which EMT transcription factor SNAI1 exerts its pro-stemness effects in cancer cells, demonstrating its potential as a stem cell-directed target for therapy. In vitro and in vivo, mesoporous silica nanoparticle-mediated SNAI1 knockdown resulted in restoration of let-7 miRNA, inhibiting stemness and reducing tumor burden. Our studies validate in vivo nanoparticle-delivered RNAi targeting the SNAI1/let-7 axis as a clinically relevant approach.

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α-Mangostin Suppresses the Viability and Epithelial-Mesenchymal Transition of Pancreatic Cancer Cells by Downregulating the PI3K/Akt Pathway

BioMed Research International ◽

10.1155/2014/546353 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 27

Author(s):

Qinhong Xu ◽

Jiguang Ma ◽

Jianjun Lei ◽

Wanxing Duan ◽

Liang Sheng ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Complementary Alternative Medicine ◽

Akt Pathway ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Matrigel Invasion ◽

Pancreatic Cancer Cells

α-Mangostin, a natural product isolated from the pericarp of the mangosteen fruit, has been shown to inhibit the growth of tumor cells in various types of cancers. However, the underlying molecular mechanisms are largely unclear. Here, we report thatα-mangostin suppressed the viability and epithelial-mesenchymal transition (EMT) of pancreatic cancer cells through inhibition of the PI3K/Akt pathway. Treatment of pancreatic cancer BxPc-3 and Panc-1 cells withα-mangostin resulted in loss of cell viability, accompanied by enhanced cell apoptosis, cell cycle arrest at G1 phase, and decrease of cyclin-D1. Moreover, Transwell and Matrigel invasion assays showed thatα-mangostin significantly reduced the migration and invasion of pancreatic cancer cells. Consistent with these results,α-mangostin decreased the expression of MMP-2, MMP-9, N-cadherin, and vimentin and increased the expression of E-cadherin. Furthermore, we found thatα-mangostin suppressed the activity of the PI3K/Akt pathway in pancreatic cancer cells as demonstrated by the reduction of the Akt phosphorylation byα-mangostin. Finally,α-mangostin significantly inhibited the growth of BxPc-3 tumor mouse xenografts. Our results suggest thatα-mangostin may be potentially used as a novel adjuvant therapy or complementary alternative medicine for the management of pancreatic cancers.

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Doxorubicin-Resistant TNBC Cells Exhibit Rapid Growth with Cancer Stem Cell-like Properties and EMT Phenotype, Which Can Be Transferred to Parental Cells through Autocrine Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms222212438 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12438

Author(s):

Anjugam Paramanantham ◽

Eun-Joo Jung ◽

Hye-Jung Kim ◽

Bae-Kwon Jeong ◽

Jin-Myung Jung ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Morphological Changes ◽

Autocrine Signaling ◽

Mesenchymal Transition ◽

Doxorubicin Resistance ◽

Cancer Dormancy ◽

Resistance To Doxorubicin

Emerging evidence suggests that breast cancer stem cells (BCSCs), and epithelial–mesenchymal transition (EMT) may be involved in resistance to doxorubicin. However, it is unlear whether the doxorubicin-induced EMT and expansion of BCSCs is related to cancer dormancy, or outgrowing cancer cells with maintaining resistance to doxorubicin, or whether the phenotypes can be transferred to other doxorubicin-sensitive cells. Here, we characterized the phenotype of doxorubicin-resistant TNBC cells while monitoring the EMT process and expansion of CSCs during the establishment of doxorubicin-resistant MDA-MB-231 human breast cancer cells (DRM cells). In addition, we assessed the potential signaling associated with the EMT process and expansion of CSCs in doxorubicin-resistance of DRM cells. DRM cells exhibited morphological changes from spindle-shaped MDA-MB-231 cells into round-shaped giant cells. They exhibited highly proliferative, EMT, adhesive, and invasive phenotypes. Molecularly, they showed up-regulation of Cyclin D1, mesenchymal markers (β-catenin, and N-cadherin), MMP-2, MMP-9, ICAM-1 and down-regulation of E-cadherin. As the molecular mechanisms responsible for the resistance to doxorubicin, up-regulation of EGFR and its downstream signaling, were suggested. AKT and ERK1/2 expression were also increased in DRM cells with the advancement of resistance to doxorubicin. Furthermore, doxorubicin resistance of DRM cells can be transferred by autocrine signaling. In conclusion, DRM cells harbored EMT features with CSC properties possessing increased proliferation, invasion, migration, and adhesion ability. The doxorubicin resistance, and doxorubicin-induced EMT and CSC properties of DRM cells, can be transferred to parental cells through autocrine signaling. Lastly, this feature of DRM cells might be associated with the up-regulation of EGFR.

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Cellular and Molecular Mechanisms of Pristimerin in Cancer Therapy: Recent Advances

Frontiers in Oncology ◽

10.3389/fonc.2021.671548 ◽

2021 ◽

Vol 11 ◽

Author(s):

Run-Ze Chen ◽

Fei Yang ◽

Min Zhang ◽

Zhi-Gang Sun ◽

Nan Zhang

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Quinone Methide ◽

Molecular Signaling ◽

Mesenchymal Transition ◽

Advantages And Disadvantages ◽

Anti Cancer

Seeking an efficient and safe approach to eliminate tumors is a common goal of medical fields. Over these years, traditional Chinese medicine has attracted growing attention in cancer treatment due to its long history. Pristimerin is a naturally occurring quinone methide triterpenoid used in traditional Chinese medicine to treat various cancers. Recent studies have identified alterations in cellular events and molecular signaling targets of cancer cells under pristimerin treatment. Pristimerin induces cell cycle arrest, apoptosis, and autophagy to exhibit anti-proliferation effects against tumors. Pristimerin also inhibits the invasion, migration, and metastasis of tumor cells via affecting cell adhesion, cytoskeleton, epithelial-mesenchymal transition, cancer stem cells, and angiogenesis. Molecular factors and pathways are associated with the anti-cancer activities of pristimerin. Furthermore, pristimerin reverses multidrug resistance of cancer cells and exerts synergizing effects with other chemotherapeutic drugs. This review aims to discuss the anti-cancer potentials of pristimerin, emphasizing multi-targeted biological and molecular regulations in cancers. Further investigations and clinical trials are warranted to understand the advantages and disadvantages of pristimerin treatment much better.

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Caffeic Acid Phenethyl Ester Inhibits Epithelial-Mesenchymal Transition of Human Pancreatic Cancer Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/270906 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 5

Author(s):

Ming-Jen Chen ◽

Shou-Chuan Shih ◽

Horng-Yuan Wang ◽

Ching-Chung Lin ◽

Chia-Yuan Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Caffeic Acid ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Caffeic Acid Phenethyl Ester ◽

Human Pancreatic Cancer ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells ◽

Migration Potential

Background. This study aimed to investigate the effect of propolis component caffeic acid phenethyl ester (CAPE) on epithelial-mesenchymal transition (EMT) of human pancreatic cancer cells and the molecular mechanisms underlying these effects.Methods. The transforming growth factorβ(TGF-β-) induced EMT in human pancreatic PANC-1 cancer cells was characterized by observation of morphology and the expression of E-cadherin and vimentin by western blotting. The migration potential was estimated with wound closure assay. The expression of transcriptional factors was measured by quantitative RT-PCR and immunocytochemistry staining. The orthotopic pancreatic cancer xenograft model was used forin vivoassessment.Results. The overexpression of vimentin was attenuated by CAPE, and the alteration in morphology from polygonal to spindle shape was partially reversed by CAPE. Furthermore, CAPE delayed the TGF-β-stimulated migration potential. CAPE treatment did not reduce the expression levels of Smad 2/3, Snail 1, and Zeb 1 but inhibited the expression of transcriptional factor Twist 2. By using an orthotopic pancreatic cancer model, CAPE suppressed the expression of Twist 2 and growth of PANC-1 xenografts without significant toxicity.Conclusion. CAPE could inhibit the orthotopic growth and EMT of pancreatic cancer PANC-1 cells accompanied by downregulation of vimentin and Twist 2 expression.

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Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

Oncogene ◽

10.1038/s41388-020-01432-7 ◽

2020 ◽

Vol 39 (39) ◽

pp. 6139-6156 ◽

Cited By ~ 3

Author(s):

Qinyao Wei ◽

Yun Qian ◽

Jun Yu ◽

Chi Chun Wong

Keyword(s):

Cancer Cells ◽

Tumor Metastasis ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Molecular Targets ◽

Mesenchymal Transition ◽

Therapeutic Implications ◽

Metastatic Cascade ◽

Metastatic Colonization

Abstract Tumor metastasis is the major cause of mortality from cancer. Metabolic rewiring and the metastatic cascade are highly intertwined, co-operating to promote multiple steps of cancer metastasis. Metabolites generated by cancer cells influence the metastatic cascade, encompassing epithelial-mesenchymal transition (EMT), survival of cancer cells in circulation, and metastatic colonization at distant sites. A variety of molecular mechanisms underlie the prometastatic effect of tumor-derived metabolites, such as epigenetic deregulation, induction of matrix metalloproteinases (MMPs), promotion of cancer stemness, and alleviation of oxidative stress. Conversely, metastatic signaling regulates expression and activity of rate-limiting metabolic enzymes to generate prometastatic metabolites thereby reinforcing the metastasis cascade. Understanding the complex interplay between metabolism and metastasis could unravel novel molecular targets, whose intervention could lead to improvements in the treatment of cancer. In this review, we summarized the recent discoveries involving metabolism and tumor metastasis, and emphasized the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these aberrant situations in cancer.

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Snail Enhances Glycolysis in the Epithelial-Mesenchymal Transition Process by Targeting FBP1 in Gastric Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000480314 ◽

2017 ◽

Vol 43 (1) ◽

pp. 31-38 ◽

Cited By ~ 17

Author(s):

Jie Yu ◽

Jing Li ◽

Yong Chen ◽

Wenmiao Cao ◽

Yuanyuan Lu ◽

...

Keyword(s):

Gastric Cancer ◽

Glucose Metabolism ◽

Protein Level ◽

Cancer Metabolism ◽

Epithelial Mesenchymal Transition ◽

Aerobic Glycolysis ◽

Transcriptional Level ◽

Mesenchymal Transition ◽

Cancer Tissues ◽

The Impact

Background: Snail is a key regulator of epithelial-mesenchymal transition (EMT) in cancer. However, the regulatory role and underlying mechanisms of Snail in gastric cancer metabolism are unknown. In this study, we characterized the regulation of aerobic glycolysis by Snail in gastric cancer. Methods: The impact of Snail on glucose metabolism was studied in vitro. Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we further analyzed the correlation between SUVmax and Snail expression in gastric cancer tissues. Results: Increased expression of Snail promoted lactate production, glucose utilization, and decreased FBP1 expression at both mRNA and protein level. The expression level of Snail was positively associated with SUVmax in gastric cancer patients (P=0.022). Snail and FBP1 expression were inversely correlated at both mRNA and protein level (P=0.002 and P=0.015 respectively) in gastric cancer tissues. Further studies demonstrated that Snail inhibited the FBP1 gene expression at the transcriptional level. Restoring FBP1 expression reversed the effects of glycolysis and EMT induced by Snail in gastric cancer cells. Conclusions: Our results thus reveal that Snail serves as a positive regulator of glucose metabolism through regulation of the FBP1 in gastric cancer. Disrupting the Snail-FBP1 signaling axis may be effective to prevent primary tumor EMT and glycolysis process.

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