scholarly journals Molecular Mechanisms Associated with ROR1-Mediated Drug Resistance: Crosstalk with Hippo-YAP/TAZ and BMI-1 Pathways

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 812 ◽  
Author(s):  
Hanna Karvonen ◽  
Harlan Barker ◽  
Laura Kaleva ◽  
Wilhelmiina Niininen ◽  
Daniela Ungureanu
Keyword(s):  
Drug Resistance ◽  
Disease Progression ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Treatment Resistance ◽  
Orphan Receptor ◽  
Oncogenic Signaling ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
Signaling Activation

Signaling via the Wnt-related receptor tyrosine kinase-like orphan receptor 1 (ROR1) triggers tumorigenic features associated with cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT), while aberrant expression of ROR1 is strongly linked to advanced disease progression and chemoresistance. Several recent studies have shown that Wnt5a binding to ROR1 promotes oncogenic signaling by activating multiple pathways such as RhoA/Rac1 GTPases and PI3K/AKT, which in turn could induce transcriptional coactivator YAP/TAZ or polycomb complex protein BMI-1 signaling, respectively, to sustain stemness, metastasis and ultimately drug-resistance. These data point towards a new feedback loop during cancer development, linking Wnt5a-ROR1 signaling activation to YAP/TAZ or BMI-1 upregulation that could play an important role in disease progression and treatment resistance. This review focuses on the crosstalk between Wnt5a-ROR1 and YAP/TAZ or the BMI-1 signaling network, together with the current advancements in targeted strategies for ROR1-positive cancers.

scholarly journals A novel homeostatic loop of sorcin drives paclitaxel-resistance and malignant progression via Smad4/ZEB1/miR-142-5p in human ovarian cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Jinguo Zhang ◽  
Wencai Guan ◽  
Xiaolin Xu ◽  
Fanchen Wang ◽  
Xin Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Calcium Binding ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Progression ◽  
Bioinformatics Analyses ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
E Box

AbstractThe primary chemotherapy of ovarian cancer (OC) often acquires chemoresistance. Sorcin (SRI), a soluble resistance-related calcium-binding protein, has been reported to be an oncogenic protein in cancer. However, the molecular mechanisms of SRI regulation and the role and aberrant expression of SRI in chemoresistant OC remain unclear. Here, we identified SRI as a key driver of paclitaxel (PTX)-resistance and explored its regulatory mechanism. Using transcriptome profiles, qRT-PCR, proteomics, Western blot, immunohistochemistry, and bioinformatics analyses, we found that SRI was overexpressed in PTX-resistant OC cells and the overexpression of SRI was related to the poor prognosis of patients. SRI was a key molecule required for growth, migration, and PTX-resistance in vitro and in vivo and was involved in epithelial–mesenchymal transition (EMT) and stemness. Mechanistic studies showed that miR-142-5p directly bound to the 3ʹ-UTR of SRI to suppress its expression, whereas a transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) inhibited the transcription of miR-142-5p by directly binding to the E-box fragment in the miR-142 promoter region. Furthermore, ZEB1 was negatively regulated by SRI which physically interacted with Smad4 to block its translocation from the cytosol to the nucleus. Taken together, our findings unveil a novel homeostatic loop of SRI that drives the PTX-resistance and malignant progression via Smad4/ZEB1/miR-142-5p in human OC. Targeting this SRI/Smad4/ZEB1/miR-142-5p loop may reverse the PTX-resistance.

scholarly journals PGC-1α Suppresses the Activation of TGF-β/Smad Signaling via Targeting TGFβRI Downregulation by let-7b/c Upregulation

2019 ◽  
Vol 20 (20) ◽  
pp. 5084 ◽  
Author(s):  
Hoon-In Choi ◽  
Jung Sun Park ◽  
Dong-Hyun Kim ◽  
Chang Seong Kim ◽  
Eun Hui Bae ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Kidney Diseases ◽  
Peroxisome Proliferator ◽  
Major Pathway ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mesenchymal Transition ◽  
Smad Signaling ◽  
Smad Signaling Pathway ◽  
Signaling Activation

TGF-β/Smad signaling is a major pathway in progressive fibrotic processes, and further studies on the molecular mechanisms of TGF-β/Smad signaling are still needed for their therapeutic targeting. Recently, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) was shown to improve renal fibrosis, making it an attractive target for chronic kidney diseases (CKDs). Here, we show the mechanism by which PGC-1α regulates the TGF-β/Smad signaling pathway using HK-2 cell lines stably overexpressing empty vector (mock cells) or human PGC1α (PGC1α cells). Stable PGC-1α overexpression negatively regulated the expression of TGF-β-induced epithelial-mesenchymal transition (EMT) markers (fibronectin, E-cadherin, vimentin, and α-SMA) and EMT-related transcription factors (Snail and Slug) compared to mock cells, inhibiting fibrotic progression. Interestingly, among molecules upstream of Smad2/3 activation, the gene expression of only TGFβRI, but not TGFβRII, was downregulated in PGC-1α cells. In addition, the downregulation of TGFβRI by PGC-1α was associated with the upregulation of let-7b/c, miRNA for which the 3′ untranslated region (UTR) of TGFβRI contains a binding site. In conclusion, PGC-1α suppresses TGF-β/Smad signaling activation via targeting TGFβRI downregulation by let-7b/c upregulation.

Epithelial-mesenchymal transition and H2O2 signaling – a driver of disease progression and a vulnerability in cancers

2022 ◽  
Vol 0 (0) ◽  
Author(s):  
Anna V. Milton ◽  
David B. Konrad
Keyword(s):  
Quality Of Life ◽  
Overall Survival ◽  
Drug Resistance ◽  
Disease Progression ◽  
Posttranslational Modifications ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Anticancer Treatment

Abstract Mutation-selective drugs constitute a great advancement in personalized anticancer treatment with increased quality of life and overall survival in cancers. However, the high adaptability and evasiveness of cancers can lead to disease progression and the development of drug resistance, which cause recurrence and metastasis. A common characteristic in advanced neoplastic cancers is the epithelial-mesenchymal transition (EMT) which is strongly interconnected with H2O2 signaling, increased motility and invasiveness. H2O2 relays its signal through the installation of oxidative posttranslational modifications on cysteines. The increased H2O2 levels that are associated with an EMT confer a heightened sensitivity towards the induction of ferroptosis as a recently discovered vulnerability.

scholarly journals Dysregulation of Fra1 expression by Wnt/β-catenin signalling promotes glioma aggressiveness through epithelial–mesenchymal transition

2017 ◽  
Vol 37 (2) ◽  
Author(s):  
Li Zhang ◽  
Huaijun Liu ◽  
Xiaodan Mu ◽  
Jianling Cui ◽  
Zhigang Peng
Keyword(s):  
Malignant Disease ◽  
Molecular Mechanisms ◽  
Cisplatin Resistance ◽  
Epithelial Mesenchymal Transition ◽  
Glioma Cells ◽  
Human Glioma ◽  
Invasion And Metastasis ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
Novel Therapeutic Strategies

Aberrant expression of Fos-related antigen-1 (Fra1) is commonly elevated in various malignant cancers and is strongly implicated in invasion and metastasis. However, the molecular mechanisms underlying its dysregulation in human glioma remain poorly understood. In the present study, we demonstrate that up-regulation of Fra1 plays a crucial role in the glioma aggressiveness and epithelial–mesenchymal transition (EMT) activated by Wnt/β-catenin signal pathway. In glioma cells, activation of Wnt/β-catenin signalling by Wnt3a administration obviously induced EMT and directly activated the transcription of Fra1. Phenotype experiments revealed that up-regulation of Fra1 induced by Wnt/β-catenin signalling drove the EMT of glioma cells. Furthermore, it was found that the cisplatin resistance acquired by Wnt/β-catenin signalling activation depended on increased expression of Fra1. Analysis of clinical specimens verified a positive correlation between Fra1 and β-catenin as well as a poor prognosis in glioma patients with double-high expressions of them. These findings indicate that an aberrant Wnt/β-catenin signalling leads to the EMT and drug resistance of glioma via Fra1 induction, which suggests novel therapeutic strategies for the malignant disease.

scholarly journals Mechanistic Insights Delineating the Role of Cholesterol in Epithelial Mesenchymal Transition and Drug Resistance in Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Naaziyah Abdulla ◽  
C. Theresa Vincent ◽  
Mandeep Kaur
Keyword(s):  
Drug Resistance ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Cholesterol Metabolism ◽  
Cholesterol Content ◽  
Multi Drug Resistance ◽  
Mesenchymal Transition ◽  
Proposed Model

Despite the significant advancements made in targeted anti-cancer therapy, drug resistance constitutes a multifaceted phenomenon leading to therapy failure and ultimately mortality. Emerging experimental evidence highlight a role of cholesterol metabolism in facilitating drug resistance in cancer. This review aims to describe the role of cholesterol in facilitating multi-drug resistance in cancer. We focus on specific signaling pathways that contribute to drug resistance and the link between these pathways and cholesterol. Additionally, we briefly discuss the molecular mechanisms related to the epithelial-mesenchymal transition (EMT), and the documented link between EMT, metastasis and drug resistance. We illustrate this by specifically focusing on hypoxia and the role it plays in influencing cellular cholesterol content following EMT induction. Finally, we provide a proposed model delineating the crucial role of cholesterol in EMT and discuss whether targeting cholesterol could serve as a novel means of combatting drug resistance in cancer progression and metastasis.

scholarly journals The Role of the Receptor Tyrosine Kinase Axl in Carcinogenesis and Development of Therapeutic Resistance: An Overview of Molecular Mechanisms and Future Applications

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1521
Author(s):  
Martha Wium ◽  
Aderonke F. Ajayi-Smith ◽  
Juliano D. Paccez ◽  
Luiz F. Zerbini
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Cancer Progression ◽  
Receptor Tyrosine Kinase ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Chemotherapeutic Agents ◽  
Mesenchymal Transition ◽  
Development Of Resistance

Resistance to chemotherapeutic agents by cancer cells has remained a major obstacle in the successful treatment of various cancers. Numerous factors such as DNA damage repair, cell death inhibition, epithelial–mesenchymal transition, and evasion of apoptosis have all been implicated in the promotion of chemoresistance. The receptor tyrosine kinase Axl, a member of the TAM family (which includes TYRO3 and MER), plays an important role in the regulation of cellular processes such as proliferation, motility, survival, and immunologic response. The overexpression of Axl is reported in several solid and hematological malignancies, including non-small cell lung, prostate, breast, liver and gastric cancers, and acute myeloid leukaemia. The overexpression of Axl is associated with poor prognosis and the development of resistance to therapy. Reports show that Axl overexpression confers drug resistance in lung cancer and advances the emergence of tolerant cells. Axl is, therefore, an important candidate as a prognostic biomarker and target for anticancer therapies. In this review, we discuss the consequence of Axl upregulation in cancers, provide evidence for its role in cancer progression and the development of drug resistance. We will also discuss the therapeutic potential of Axl in the treatment of cancer.

scholarly journals ENC1 Facilitates Colorectal Carcinoma Tumorigenesis and Metastasis via JAK2/STAT5/AKT Axis-Mediated Epithelial Mesenchymal Transition and Stemness

2021 ◽  
Vol 9 ◽  
Author(s):  
Ying Cui ◽  
Jiani Yang ◽  
Yibing Bai ◽  
QingWei Li ◽  
Yuanfei Yao ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Actin Binding ◽  
Phenotypic Traits ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
Computation Analysis

Ectodermal neural cortex 1 (ENC1) is an actin-binding protein and has been known to be upregulated in several cancers, but the molecular mechanisms through which it contributes to the pathology of CRC have largely been elusive. We utilized data mining and validated the aberrant expression of ENC1, following which phenotypic traits of malignancy were assessed in vitro. Ruxolitinib was used as a surrogate to compare the effects of ENC1 expression and silencing on the JAK-STAT-AKT pathway. In vivo models were employed to confirm the in vitro observations. Computation analysis, strengthened by in situ and in vitro data, confirmed the overexpression of ENC1 in CRC and predicted a poor prognosis, while enhanced cell proliferation, invasion, migration, EMT, and stemness were associated with ENC1 overexpression. Silencing of ENC1 downregulated the phenotypes. Additionally, silencing of ENC1 significantly reduced the activation of JAK2 and consequent activation of STAT5 and AKT comparable to ruxolitinib inhibition of JAK2. Silencing of ENC1 resulted in lesser tumor volumes and fewer numbers of tumors, in vivo. These data suggest that ENC1 induces CRC through the JAK2-STAT5-AKT axis. ENC1 is a suitable diagnostic marker for CRC detection, and ENC1 targeting therapies may suppress CRC progression.

MiR-597 Targeting 14-3-3σ Enhances Cellular Invasion and EMT in Nasopharyngeal Carcinoma Cells

2019 ◽  
Vol 12 (2) ◽  
pp. 105-114 ◽  
Author(s):  
Lisha Xie ◽  
Tao Jiang ◽  
Ailan Cheng ◽  
Ting Zhang ◽  
Pin Huang ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Cell Lines ◽  
Western Blotting ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Suppressor Gene ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Downstream Target ◽  
Before And After

Background: Alterations in microRNAs (miRNAs) are related to the occurrence of nasopharyngeal carcinoma (NPC) and play an important role in the molecular mechanism of NPC. Our previous studies show low expression of 14-3-3σ (SFN) is related to the metastasis and differentiation of NPC, but the underlying molecular mechanisms remain unclear. Methods: Through bioinformatics analysis, we find miR-597 is the preferred target miRNA of 14-3-3σ. The expression level of 14-3-3σ in NPC cell lines was detected by Western blotting. The expression of miR-597 in NPC cell lines was detected by qRT-PCR. We transfected miR-597 mimic, miR-597 inhibitor and 14-3-3σ siRNA into 6-10B cells and then verified the expression of 14-3-3σ and EMT related proteins, including E-cadherin, N-cadherin and Vimentin by western blotting. The changes of migration and invasion ability of NPC cell lines before and after transfected were determined by wound healing assay and Transwell assay. Results: miR-597 expression was upregulated in NPC cell lines and repaired in related NPC cell lines, which exhibit a potent tumor-forming effect. After inhibiting the miR-597 expression, its effect on NPC cell line was obviously decreased. Moreover, 14-3-3σ acts as a tumor suppressor gene and its expression in NPC cell lines is negatively correlated with miR-597. Here 14-3-3σ was identified as a downstream target gene of miR-597, and its downregulation by miR-597 drives epithelial-mesenchymal transition (EMT) and promotes the migration and invasion of NPC. Conclusion: Based on these findings, our study will provide theoretical and experimental evidences for molecular targeted therapy of NPC.

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.

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