Potential Roles of Iridoid Glycosides and Their Underlying Mechanisms against Diverse Cancer Growth and Metastasis: Do They Have an Inhibitory Effect on Cancer Progression?

Iridoids are glycosides found in plants, having inherent roles in defending them against infection by viruses and microorganisms, and in the rapid repair of damaged areas. The emerging roles of iridoid glycosides on pharmacological properties have aroused the curiosity of many researchers, and studies undertaken indicate that iridoid glycosides exert inhibitory effects in numerous cancers. This review focuses on the roles and the potential mechanism of iridoid glycosides at each stage of cancer development such as proliferation, epithelial mesenchymal transition (EMT), migration, invasion and angiogenesis. Overall, the reviewed literature indicates that iridoid glycosides inhibit cancer growth by inducing cell cycle arrest or by regulating apoptosis-related signaling pathways. In addition, iridoid glycosides suppress the expression and activity of matrix metalloproteinases (MMPs), resulting in reduced cancer cell migration and invasiveness. The antiangiogenic mechanism of iridoid glycosides was found to be closely related to the transcriptional regulation of pro-angiogenic factors, i.e., vascular endothelial growth factors (VEGFs) and cluster of differentiation 31 (CD31). Taken together, these results indicate the therapeutic potential of iridoid glycosides to alleviate or prevent rapid cancer progression and metastasis.

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Roles of MicroRNA-34a in Epithelial to Mesenchymal Transition, Competing Endogenous RNA Sponging and Its Therapeutic Potential

International Journal of Molecular Sciences ◽

10.3390/ijms20040861 ◽

2019 ◽

Vol 20 (4) ◽

pp. 861 ◽

Cited By ~ 9

Author(s):

Dongsong Nie ◽

Jiewen Fu ◽

Hanchun Chen ◽

Jingliang Cheng ◽

Junjiang Fu

Keyword(s):

Cancer Therapy ◽

Cancer Progression ◽

Noncoding Rna ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Therapeutic Potential ◽

Circular Rna ◽

Signal Pathways ◽

Competing Endogenous Rna ◽

Mesenchymal Transition

MicroRNA-34a (miR-34a), a tumor suppressor, has been reported to be dysregulated in various human cancers. MiR-34a is involves in certain epithelial-mesenchymal transition (EMT)-associated signal pathways to repress tumorigenesis, cancer progression, and metastasis. Due to the particularity of miR-34 family in tumor-associated EMT, the significance of miR-34a is being increasingly recognized. Competing endogenous RNA (ceRNA) is a novel concept involving mRNA, circular RNA, pseudogene transcript, and long noncoding RNA regulating each other’s expressions using microRNA response elements to compete for the binding of microRNAs. Studies showed that miR-34a is efficient for cancer therapy. Here, we provide an overview of the function of miR-34a in tumor-associated EMT. ceRNA hypothesis plays an important role in miR-34a regulation in EMT, cancer progression, and metastasis. Its potential roles and challenges as a microRNA therapeutic candidate are discussed. As the negative effect on cancer progression, miR-34a should play crucial roles in clinical diagnosis and cancer therapy.

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Knockdown lncRNA DLEU1 Inhibits Gliomas Progression and Promotes Temozolomide Chemosensitivity by Regulating Autophagy

Frontiers in Pharmacology ◽

10.3389/fphar.2020.560543 ◽

2020 ◽

Vol 11 ◽

Author(s):

Qiao-Li Lv ◽

Li-Chong Wang ◽

Dang-Chi Li ◽

Qian-Xia Lin ◽

Xiao-Li Shen ◽

...

Keyword(s):

Epithelial Mesenchymal Transition ◽

Glioma Cells ◽

Migration And Invasion ◽

Normal Brain ◽

Mesenchymal Transition ◽

Cycle Arrest ◽

Underlying Mechanisms ◽

Multiple Drugs ◽

Emt Markers ◽

Brain Tissues

Gliomas are the most fatal malignant cerebral tumors. Temozolomide (TMZ), as the primary chemotherapy drug, has been widely used in clinics. However, resistance of TMZ still remains to poor defined. LncRNAs have been reported to play crucial roles in progression of various cancers and resistance of multiple drugs. However, the biological function and underlying mechanisms of most lncRNAs in glioma still remains unclear. Based on the TCGA database, a total of 94 differentially expressed lncRNAs, including 16 up-regulated genes and 78 downregulated genes were identified between gliomas and normal brain tissues. Subsequently, lncRNA DLEU1, HOTAIR, and LOC00132111 were tested to be significantly related to overall survival (OS) between high- and low-expression groups. Additionally, we verified that lncRNA DLEU1 was high expressed in 108 gliomas, compared with 19 normal brain tissues. And high expression of lncRNA DLEU1 predicted a poor prognosis (HR = 1.703, 95%CI: 1.133–2.917, p-value = 0.0159). Moreover, functional assays revealed that knockdown of lncRNA DLEU1 could suppress the proliferation by inducing cell cycle arrest at G1 phase and reducing the S phase by down-regulating the CyclinD1 and p-AKT, as the well as migration and invasion by inhibiting the epithelial–mesenchymal transition (EMT) markers, such as ZEB1, N-cadherin, β-catenin and snail in glioma cells. Furthermore, silencing lncRNA DLEU1 suppressed TMZ-activated autophagy via regulating the expression of P62 and LC3, and promoted sensitivity of glioma cells to TMZ by triggering apoptosis. Conclusively, our study indicated that lncRNA DLEU1 might perform as a prognostic potential target and underlying therapeutic target for sensitivity of glioma to TMZ.

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SNHG5 inhibits the progression of EMT through the ubiquitin-degradation of MTA2 in oesophageal cancer

Carcinogenesis ◽

10.1093/carcin/bgaa110 ◽

2020 ◽

Author(s):

Sisi Wei ◽

Shiping Sun ◽

Xinliang Zhou ◽

Cong Zhang ◽

Xiaoya Li ◽

...

Keyword(s):

Cell Lines ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Survival Rates ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Underlying Mechanisms ◽

And Function

Abstract A substantial fraction of transcripts are known as long noncoding RNAs (lncRNAs), and these transcripts play pivotal roles in the development of cancer. However, little information has been published regarding the functions of lncRNAs in oesophageal squamous cell carcinoma (ESCC) and the underlying mechanisms. In our previous studies, we demonstrated that small nucleolar RNA host gene 5 (SNHG5), a known lncRNA, is dysregulated in gastric cancer (GC). In this study, we explored the expression and function of SNHG5 in development of ESCC. SNHG5 was found to be downregulated in human ESCC tissues and cell lines, and this downregulation was associated with cancer progression, clinical outcomes and survival rates of ESCC patients. Furthermore, we also found that overexpression of SNHG5 significantly inhibited the proliferation, migration and invasion of ESCC cells in vivo and in vitro. Notably, we found that metastasis-associated protein 2 (MTA2) was pulled down by SNHG5 in ESCC cells using RNA pulldown assay. We also found that SNHG5 reversed the epithelial–mesenchymal transition by interacting with MTA2. In addition, overexpression of SNHG5 downregulated the transcription of MTA2 and caused its ubiquitin-mediated degradation. Thus, overexpression of MTA2 partially abrogated the effect of SNHG5 in ESCC cell lines. Furthermore, we found that MTA2 mRNA expression was significantly elevated in ESCC specimens, and a negative correlation between SNHG5 and MTA2 expression was detected. Overall, this study demonstrated, for the first time, that SNHG5-regulated MTA2 functions as an important player in the progression of ESCC and provide a new potential therapeutic strategy for ESCC.

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YAP-Dependent BiP Induction Is Involved in Nicotine-Mediated Oral Cancer Malignancy

Cells ◽

10.3390/cells10082080 ◽

2021 ◽

Vol 10 (8) ◽

pp. 2080

Author(s):

Chu-Yen Chien ◽

Ying-Chen Chen ◽

Chia-Chen Hsu ◽

Yu-Ting Chou ◽

Shine-Gwo Shiah ◽

...

Keyword(s):

Oral Cancer ◽

Er Stress ◽

Cancer Progression ◽

Nuclear Translocation ◽

Epithelial Mesenchymal Transition ◽

Therapeutic Potential ◽

Significant Risk ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Α7 Nachr

Cigarette smoking is a significant risk factor for the development and progression of oral cancer. Previous studies have reported an association between nicotine and malignancy in oral cancer. Recent studies have also demonstrated that nicotine can induce endoplasmic reticulum (ER) stress in tumor cells. Binding immunoglobulin protein (BiP) acts as a master regulator of ER stress and is frequently overexpressed in oral cancer cell lines and tissues. However, the effect of nicotine on BiP in oral cancer is unknown. Therefore, this study aimed to evaluate the role of BiP and its underlying regulatory mechanisms in nicotine-induced oral cancer progression. Our results showed that nicotine significantly induced the expression of BiP in time- and dose-dependent manners in oral squamous cell carcinoma (OSCC) cells. In addition, BiP was involved in nicotine-mediated OSCC malignancy, and depletion of BiP expression remarkably suppressed nicotine-induced malignant behaviors, including epithelial–mesenchymal transition (EMT) change, migration, and invasion. In vivo, BiP silencing abrogated nicotine-induced tumor growth and EMT switch in nude mice. Moreover, nicotine stimulated BiP expression through the activation of the YAP-TEAD transcriptional complex. Mechanistically, we observed that nicotine regulated YAP nuclear translocation and its interaction with TEAD through α7-nAChR-Akt signaling, subsequently resulting in increased TEAD occupancy on the HSPA5 promoter and elevated promoter activity. These observations suggest that BiP is involved in nicotine-induced oral cancer malignancy and may have therapeutic potential in tobacco-related oral cancer.

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PBX1 Participated in Estrogen Mediated Bladder Cancer Progression and Chemo-Resistance through Affecting Estrogen Receptors

10.21203/rs.3.rs-810980/v1 ◽

2021 ◽

Author(s):

Yang Zhao ◽

Jizhong Che ◽

Aimin Tian ◽

Gang Zhang ◽

Yankai Xu ◽

...

Keyword(s):

Bladder Cancer ◽

Estrogen Receptors ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

High Morbidity ◽

Promoting Effect ◽

Mesenchymal Transition ◽

Survival Status ◽

Underlying Mechanisms ◽

Muscle Invasive

Abstract Bladder cancer (BCa) is a common cancer associated with high morbidity and mortality worldwide. Pre-B-cell leukemia transcription factor 1 (PBX1) has been reported to be involved in tumor progression. The aim of the study was to explore the specific role of PBX1 in BCa and its underlying mechanisms. The relative expressions of PBX1 in muscle-invasive BCa tissues and cell lines were analyzed through RT-qPCR and Western blotting. Kaplan–Meier analysis was used to analyze the relationship between PBX1 levels and survival status. Co-immunoprecipitation (CO-IP) and chromatin immunoprecipitation (ChIP)-qPCR assay were adopted to verify the interaction between PBX1 and Estrogen receptors (ERs), and explore the ER-dependent genes transcription. The results shown that PBX1 was upregulated in invasive BCa patients and BCa cells, positively associated with tumor size, lymph node metastasis, distant metastasis and poorer survival status. Overexpression of PBX1 promoted cell growth, invasion, epithelial-mesenchymal transition (EMT) process and cisplatin resistance in BCa cells, while the silence of PBX1 showed opposite effects. Further, PBX1 interacted with Estrogen receptors (ERs) and was required for the ER function. Overexpression of PBX1 aggravated the tumor-promoting effect of estrogen on BCa cells, while partially suppressed the inhibitory effects of ER antagonist AZD9496 on BCa cells. In summary, this study revealed that PBX1 participated in estrogen mediated BCa progression and chemo-resistance through binding and activating estrogen receptors. Hence, PBX1 may serve as a potential prognostic and therapeutic target for BCa treatment.

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

Cancers ◽

10.3390/cancers13071521 ◽

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.

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Roles of Non-Coding RNAs in Cervical Cancer Metastasis

Frontiers in Oncology ◽

10.3389/fonc.2021.646192 ◽

2021 ◽

Vol 11 ◽

Author(s):

Tanchun Cheng ◽

Shouguo Huang

Keyword(s):

Cervical Cancer ◽

Cancer Progression ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Interaction Network ◽

Mesenchymal Transition ◽

Complex Process ◽

Non Coding Rnas ◽

Underlying Mechanisms ◽

Huge Challenge

Metastasis remains to be a huge challenge in cancer therapy. The mechanism underlying cervical cancer metastasis is not well understood and needs to be elucidated. Recent studies have highlighted the diverse roles of non-coding RNAs in cancer progression and metastasis. Increasing numbers of miRNAs, lncRNAs and circRNAs are found to be dysregulated in cervical cancer, associated with metastasis. They have been shown to regulate metastasis through regulating metastasis-related genes, epithelial-mesenchymal transition, signaling pathways and interactions with tumor microenvironment. Moreover, miRNAs can interact with lncRNAs and circRNAs respectively during this complex process. Herein, we review literatures up to date involving non-coding RNAs in cervical cancer metastasis, mainly focus on the underlying mechanisms and highlight the interaction network between miRNAs and lncRNAs, as well as circRNAs. Finally, we discuss the therapeutic prospects.

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20(S)-ginsenoside Rh2 as agent for the treatment of LMN-CRC via regulating epithelial–mesenchymal transition

Bioscience Reports ◽

10.1042/bsr20191507 ◽

2020 ◽

Vol 40 (3) ◽

Author(s):

Yihang Yuan ◽

Jue Wang ◽

Ming Xu ◽

Yunpeng Zhang ◽

Zhiqiang Wang ◽

...

Keyword(s):

Epithelial Mesenchymal Transition ◽

Therapeutic Potential ◽

Potential Effect ◽

Therapeutic Effects ◽

Dependent Manner ◽

Ginsenoside Rh2 ◽

Mesenchymal Transition ◽

Underlying Mechanisms

Abstract The lymph node metastasis of colorectal cancer (LMN-CRC) seriously threatens the prognosis of patients. Chemotherapy, as the most common treatment, results in severe bone marrow suppression. 20(S)-ginsenoside Rh2 (SGRh2), a major effective constituent of ginseng, has demonstrated therapeutic effects on a variety of diseases, including some tumours. SGRh2 treatment had no effect on other organs. Therefore, ginsenosides are considered a safe and effective antineoplastic drug. However, the effects of SGRh2 on LMN-CRC remain unknown. The present study investigated the potential effect of SGRh2 on LMN-CRC in vitro and in vivo. SW480 and CoLo205 cell lines were treated with SGRh2. SGRh2 dose-dependently decreased CRC cell proliferation by CCK-8, colony formation and Edu assays. The Transwell and scratch assays revealed that SGRh2 inhibits the migratory and invasive abilities of CRC cells in a dose-dependent manner. Furthermore, the results of Western blotting revealed that SGRh2 decreased the expression of matrix metalloproteinase (MMP)-2 and MMP9. In terms of the underlying mechanisms, SGRh2 regulates CRC metastasis by affecting epithelial–mesenchymal transition (EMT), which significantly up-regulated epithelial biomarkers (E-cadherin) and down-regulated mesenchymal biomarkers (N-cadherin and vimentin) and EMT transcriptional factors (Smad-3, Snail-1, and Twist-1). In vivo, SGRh2 significantly inhibited LMN-CRC without affecting other normal organs. Immunohistochemical results showed that SGRh2 treats LMN-CRC by regulating EMT. These results demonstrate that SGRh2 has therapeutic potential for LMN-CRC.

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