scholarly journals The Role of p53-Mediated Signaling in the Therapeutic Response of Colorectal Cancer to 9F, a Spermine-Modified Naphthalene Diimide Derivative

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 528 ◽  
Author(s):  
Lei Gao ◽  
Chaochao Ge ◽  
Senzhen Wang ◽  
Xiaojuan Xu ◽  
Yongli Feng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Tumor Growth ◽  
Molecular Mechanisms ◽  
High Rate ◽  
Anticancer Activities ◽  
Altered Expression ◽  
Mesenchymal Transition

Colorectal cancer (CRC) is one of the most prevalent cancers due to its frequency and high rate of mortality. Polyamine-vectorized anticancer drugs possess multiple biological properties. Of these drugs, 9F has been shown to inhibit tumor growth and the metastasis of hepatocellular carcinoma. This current study aims to investigate the effects of 9F on CRC and determine its molecular mechanisms of action. Our findings demonstrate that 9F inhibits CRC cell growth by inducing apoptosis and cell cycle arrest, and suppresses migration, invasion and angiogenesis in vitro, resulting in the inhibition of tumor growth and metastasis in vivo. Based on RNA-seq data, further bioinformatic analyses suggest that 9F exerts its anticancer activities through p53 signaling, which is responsible for the altered expression of key regulators of the cell cycle, apoptosis, the epithelial-to-mesenchymal transition (EMT), and angiogenesis. In addition, 9F is more effective than amonafide against CRC. These results show that 9F can be considered as a potential strategy for CRC treatment.

scholarly journals In Vivo and In Vitro Effects of Tracheloside on Colorectal Cancer Cell Proliferation and Metastasis

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 513
Author(s):  
Min-Kyoung Shin ◽  
Yong-Deok Jeon ◽  
Seung-Heon Hong ◽  
Sa-Haeng Kang ◽  
Ji-Ye Kee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Oxidant Stress ◽  
Mesenchymal Transition ◽  
Cycle Arrest

Recent research suggests a relationship between cancer progression and oxidative mechanisms. Among the phenolic compounds such as tracheloside (TCS) are a major bioactive compound that can combat oxidant stress-related chronic diseases and that also displays anti-tumor activity. Although TCS can inhibit mammalian carcinoma, its effects on colorectal cancer (CRC) have not been clarified. The purpose of this study was to investigate the effects of TCS on the proliferation of CRC cells, the metastasis of CT26 cells, and the molecular mechanisms related to TCS in vitro and in vivo. A cell viability assay showed that TCS inhibited the proliferation of CRC cells. TCS-treated CT26 cells were associated with the upregulation of p16 as well as the downregulation of cyclin D1 and CDK4 in cell cycle arrest. In addition, TCS induced apoptosis of CT26 cells through mitochondria-mediated apoptosis and regulation of the Bcl-2 family. Expression of epithelial–mesenchymal transition (EMT) markers was regulated by TCS treatment in CT26 cells. TCS significantly inhibited the lung metastasis of CT26 cells in a mouse model. These results suggest that TCS, by inducing cell cycle arrest and apoptosis through its anti-oxidant properties, is a novel therapeutic agent that inhibits metastatic phenotypes of murine CRC cells.

scholarly journals Tumor quiescence: elevating SOX2 in diverse tumor cell types downregulates a broad spectrum of the cell cycle machinery and inhibits tumor growth

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Ethan P. Metz ◽  
Erin L. Wuebben ◽  
Phillip J. Wilder ◽  
Jesse L. Cox ◽  
Kaustubh Datta ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cell Cycle Machinery

Abstract Background Quiescent tumor cells pose a major clinical challenge due to their ability to resist conventional chemotherapies and to drive tumor recurrence. Understanding the molecular mechanisms that promote quiescence of tumor cells could help identify therapies to eliminate these cells. Significantly, recent studies have determined that the function of SOX2 in cancer cells is highly dose dependent. Specifically, SOX2 levels in tumor cells are optimized to promote tumor growth: knocking down or elevating SOX2 inhibits proliferation. Furthermore, recent studies have shown that quiescent tumor cells express higher levels of SOX2 compared to adjacent proliferating cells. Currently, the mechanisms through which elevated levels of SOX2 restrict tumor cell proliferation have not been characterized. Methods To understand how elevated levels of SOX2 restrict the proliferation of tumor cells, we engineered diverse types of tumor cells for inducible overexpression of SOX2. Using these cells, we examined the effects of elevating SOX2 on their proliferation, both in vitro and in vivo. In addition, we examined how elevating SOX2 influences their expression of cyclins, cyclin-dependent kinases (CDKs), and p27Kip1. Results Elevating SOX2 in diverse tumor cell types led to growth inhibition in vitro. Significantly, elevating SOX2 in vivo in pancreatic ductal adenocarcinoma, medulloblastoma, and prostate cancer cells induced a reversible state of tumor growth arrest. In all three tumor types, elevation of SOX2 in vivo quickly halted tumor growth. Remarkably, tumor growth resumed rapidly when SOX2 returned to endogenous levels. We also determined that elevation of SOX2 in six tumor cell lines decreased the levels of cyclins and CDKs that control each phase of the cell cycle, while upregulating p27Kip1. Conclusions Our findings indicate that elevating SOX2 above endogenous levels in a diverse set of tumor cell types leads to growth inhibition both in vitro and in vivo. Moreover, our findings indicate that SOX2 can function as a master regulator by controlling the expression of a broad spectrum of cell cycle machinery. Importantly, our SOX2-inducible tumor studies provide a novel model system for investigating the molecular mechanisms by which elevated levels of SOX2 restrict cell proliferation and tumor growth.

scholarly journals TRPC1 promotes the genesis and progression of colorectal cancer via activating CaM-mediated PI3K/AKT signaling axis

Oncogenesis ◽  
2021 ◽  
Vol 10 (10) ◽  
Author(s):  
Yang Sun ◽  
Chen Ye ◽  
Wen Tian ◽  
Wen Ye ◽  
Yuan-Yuan Gao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Tumor Growth ◽  
Cell Cycle Progression ◽  
Akt Signaling ◽  
Cycle Progression ◽  
Colorectal Tumorigenesis ◽  
Signaling Axis

AbstractTransient receptor potential canonical (TRPC) channels are the most prominent nonselective cation channels involved in various diseases. However, the function, clinical significance, and molecular mechanism of TRPCs in colorectal cancer (CRC) progression remain unclear. In this study, we identified that TRPC1 was the major variant gene of the TRPC family in CRC patients. TRPC1 was upregulated in CRC tissues compared with adjacent normal tissues and high expression of TRPC1 was associated with more aggressive tumor progression and poor overall survival. TRPC1 knockdown inhibited cell proliferation, cell-cycle progression, invasion, and migration in vitro, as well as tumor growth in vivo; whereas TRPC1 overexpression promoted colorectal tumor growth and metastasis in vitro and in vivo. In addition, colorectal tumorigenesis was significantly attenuated in Trpc1-/- mice. Mechanistically, TRPC1 could enhance the interaction between calmodulin (CaM) and the PI3K p85 subunit by directly binding to CaM, which further activated the PI3K/AKT and its downstream signaling molecules implicated in cell cycle progression and epithelial-mesenchymal transition. Silencing of CaM attenuated the oncogenic effects of TRPC1. Taken together, these results provide evidence that TRPC1 plays a pivotal oncogenic role in colorectal tumorigenesis and tumor progression by activating CaM-mediated PI3K/AKT signaling axis. Targeting TRPC1 represents a novel and specific approach for CRC treatment.

scholarly journals TMEM52B suppression promotes cancer cell survival and invasion through modulating E-cadherin stability and EGFR activity

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Yunhee Lee ◽  
Dongjoon Ko ◽  
Junghwa Yoon ◽  
Younghoon Lee ◽  
Semi Kim
Keyword(s):  
Tumor Growth ◽  
Cell Survival ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
The Cancer Genome Atlas ◽  
In Vivo Studies ◽  
Mesenchymal Transition ◽  
E Cadherin

Abstract Background TMEM52B is a novel gene broadly expressed in a variety of normal human tissues. However, the biological function of TMEM52B expression in cancer is largely unknown. Methods The effects of TMEM52B on tumor growth and metastasis were investigated in vitro and in vivo, and the underlying biological and molecular mechanisms involved in this process were evaluated. Clinical datasets from KmPlotter and The Cancer Genome Atlas (TCGA) were analyzed in relation to TMEM52B expression and function. Results Suppression of TMEM52B in colon cancer cells promoted cancer cell epithelial-mesenchymal transition (EMT), invasion, and survival in vitro. Similarly, in vivo studies showed increased tumor growth and circulating tumor cell survival (early metastasis). ERK1/2, JNK, and AKT signaling pathways were involved in TMEM52B suppression-induced invasiveness and cell survival. TMEM52B suppression promoted activation and internalization of epidermal growth factor receptor (EGFR) with enhanced downstream signaling activity, leading to enhanced cell survival and invasion. In addition, TMEM52B suppression reduced E-cadherin stability, likely due to a reduced association between it and E-cadherin, which led to enhanced β-catenin transcriptional activity. Concomitantly, TMEM52B suppression promoted generation of soluble E-cadherin fragments, contributing to the activation of EGFR. Clinical data showed that high TMEM52B expression correlated with increased patient survival in multiple types of cancer, including breast, lung, kidney, and rectal cancers, and suggested a correlation between TMEM52B and E-cadherin. Conclusions These findings suggest that TMEM52B is a novel modulator of the interplay between E-cadherin and EGFR. It is possible that TMEM52B functions as a tumor-suppressor that could potentially be used as a novel prognostic marker for cancer.

scholarly journals BRD7 Promotes Cell Proliferation and Tumor Growth Through Stabilization of c-Myc in Colorectal Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Ran Zhao ◽  
Yukun Liu ◽  
Chunchun Wu ◽  
Mengna Li ◽  
Yanmei Wei ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Cell Cycle Progression ◽  
Protein Targeting ◽  
Clinical Stage ◽  
Ubiquitin Proteasome

BRD7 functions as a crucial tumor suppressor in numerous malignancies. However, the effects of BRD7 on colorectal cancer (CRC) progression are still unknown. Here, based on the BRD7 knockout (BRD7–/–) and BRD7flox/flox (BRD7+/+) mouse models constructed in our previous work, we established an azoxymethane/dextran sodium sulfate (AOM/DSS)-induced mouse model. BRD7+/+ mice were found to be highly susceptible to AOM/DSS-induced colitis-associated CRC, and BRD7 significantly promoted cell proliferation and cell cycle G1/S transition but showed no significant effect on cell apoptosis. Furthermore, BRD7 interacted with c-Myc and stabilized c-Myc by inhibiting its ubiquitin–proteasome-dependent degradation. Moreover, restoring the expression of c-Myc in BRD7-silenced CRC cells restored cell proliferation, cell cycle progression, and tumor growth in vitro and in vivo. In addition, BRD7 and c-Myc were both significantly upregulated in CRC patients, and high expression of these proteins was associated with clinical stage and poor prognosis in CRC patients. Collectively, BRD7 functions as an oncogene and promotes CRC progression by regulating the ubiquitin–proteasome-dependent stabilization of c-Myc protein. Targeting the BRD7/c-Myc axis could be a potential therapeutic strategy for CRC.

scholarly journals HSPA4 knockdown retarded progression and development of colorectal cancer

2020 ◽  
Author(s):  
Mingliang Zhang ◽  
Weigang Dai ◽  
Zhanyu Li ◽  
Liang Tang ◽  
Jianhui Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Molecular Therapy ◽  
Cell Counting ◽  
Antibody Array ◽  
And Migration

Abstract Background: Colorectal cancer (CRC) is the third most common cancer worldwide and the fourth most common cause of cancer death. The heat shock 70kDa protein 4 (HSPA4) participate in progression and development of cancers. However, the cellular functions, potential molecular mechanisms of HSPA4 in CRC are still largely unknown. Methods: In this study, qRT-PCR and Western Blot were used to identify the constructed HSPA4 knockdown cell lines, which was further used to construct mouse xenotransplantation models. Effects of HSPA4 knockdown on cell proliferation, apoptotic, cell cycle and migration of CRC were examined using Celigo cell counting assay, Flow cytometry, wound healing assay and Transwell assay, respectively. In addition, Human Apoptosis Antibody Array was performed to explore downstream molecular mechanism of HSPA4 in CRC cells. Results: HSPA4 was overexpressed in CRC, which was positively associated with lymphatic metastasis (N value), number of Lymph node. In addition, high expression of HSPA4 predicted poor prognosis of patients with CRC. Furthermore, HSPA4 knockdown inhibit proliferation, migration, promote apoptosis, and arrest cell cycle of CRC cells in vitro. Moreover, in vivo results supported HSPA4 knockdown inhibit tumor growth. Additionally, the induction of apoptosis of CRC cells by HSPA4 knockdown required the participation of a series of apoptosis-related proteins. The downregulation of HSPA4 promoted the progression of CRC cells, which resulted in alterations of PI3K/Akt, CCND1 and CDK6 in downstream signaling pathways. Conclusions: In sum, the downregulation of HSPA4 promoted CRC and may be a potential target for molecular therapy.

scholarly journals Hspa4 Knockdown Retarded Progression and Development of Colorectal Cancer

2020 ◽  
Author(s):  
Mingliang Zhang ◽  
Weigang Dai ◽  
Zhanyu Li ◽  
Liang Tang ◽  
Jianhui Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Molecular Therapy ◽  
Cell Counting ◽  
Antibody Array ◽  
And Migration

Abstract Background Colorectal cancer (CRC) is the third most common cancer worldwide and the fourth most common cause of cancer death. The heat shock 70 kDa protein 4 (HSPA4) participate in progression and development of cancers. However, the cellular functions, potential molecular mechanisms of HSPA4 in CRC are still largely unknown. Methods In this study, qRT-PCR and Western Blot were used to identify the constructed HSPA4 knockdown cell lines, which was further used to construct mouse xenotransplantation models. Effects of HSPA4 knockdown on cell proliferation, apoptotic, cell cycle and migration of CRC were examined using Celigo cell counting assay, Flow cytometry, wound healing assay and Transwell assay, respectively. In addition, Human Apoptosis Antibody Array was performed to explore downstream molecular mechanism of HSPA4 in CRC cells. Results HSPA4 was overexpressed in CRC, which was positively associated with lymphatic metastasis (N value), number of Lymph node. In addition, high expression of HSPA4 predicted poor prognosis of patients with CRC. Furthermore, HSPA4 knockdown inhibit proliferation, migration, promote apoptosis, and arrest cell cycle of CRC cells in vitro. Moreover, in vivo results supported HSPA4 knockdown inhibit tumor growth. Additionally, the induction of apoptosis of CRC cells by HSPA4 knockdown required the participation of a series of apoptosis-related proteins. The downregulation of HSPA4 promoted the progression of CRC cells, which resulted in alterations of PI3K/Akt, CCND1 and CDK6 in downstream signaling pathways. Conclusions In sum, the downregulation of HSPA4 promoted CRC and may be a potential target for molecular therapy.

NLRP3 Promotes Colorectal Cancer Cell Proliferation and Metastasis via Regulating Epithelial Mesenchymal Transformation

2020 ◽  
Vol 20 (7) ◽  
pp. 820-827 ◽  
Author(s):  
Xinyu Shao ◽  
Zhiyi Lei ◽  
Chunli Zhou
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Inflammatory Responses ◽  
Venous Invasion ◽  
Tnm Staging ◽  
Mesenchymal Transition ◽  
Mesenchymal Transformation

Background: Nucleotide-binding domain Leucine-rich Repeat Protein 3 (NLRP3) plays a regulatory role in the immune and inflammatory responses, and has been implicated in Colorectal Cancer (CRC) progression and metastasis. However, the underlying molecular mechanisms have not been fully elucidated. Methods: In this study, we analyzed the expression levels of NLRP3 in human CRC tissues, and performed functional assays in CRC cell lines and a subcutaneous tumor model to elucidate its role in the development and progression of CRC. Results: In this study, we found that NLRP3 was significantly upregulated in human CRC tissues and was associated with tumor size and invasion, lymph node metastasis, venous invasion, neural invasion and TNM staging. Furthermore, knockdown of NLRP3 in CRC cells inhibited their migration and growth in vitro and in vivo, and reversed Epithelial-Mesenchymal Transition (EMT) in vitro. Conclusion: Our findings indicate that NLRP3 likely regulates CRC metastasis by activating the EMT program, and is a potential therapeutic target.

scholarly journals Haprolid Inhibits Tumor Growth of Hepatocellular Carcinoma through Rb/E2F and Akt/mTOR Inhibition

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 615
Author(s):  
Jun Xing ◽  
Vikas Bhuria ◽  
Khac Cuong Bui ◽  
Mai Ly Thi Nguyen ◽  
Zexi Hu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Tumor Growth ◽  
Molecular Mechanisms ◽  
Palliative Therapy ◽  
Migration And Invasion ◽  
Mtor Inhibition ◽  
Mesenchymal Transition ◽  
Hcc Cells

Background: Hepatocellular carcinoma (HCC) represents a major health burden with limited curative treatment options. There is a substantial unmet need to develop innovative approaches to impact the progression of advanced HCC. Haprolid is a novel natural component isolated from myxobacteria. Haprolid has been reported as a potent selective cytotoxin against a panel of tumor cells in recent studies including HCC cells. The aims of this study are to evaluate the antitumor effect of haprolid in HCC and to understand its underlying molecular mechanisms. Methods: The efficacy of haprolid was evaluated in human HCC cell lines (Huh-7, Hep3B and HepG2) and xenograft tumors (NMRI-Foxn1nu mice with injection of Hep3B cells). Cytotoxic activity of haprolid was determined by the WST-1 and crystal violet assay. Wound healing, transwell and tumorsphere assays were performed to investigate migration and invasion of HCC cells. Apoptosis and cell-cycle distribution were measured by flow cytometry. The effects of haprolid on the Rb/E2F and Akt/mTOR pathway were examined by immunoblotting and immunohistochemistry. Results: haprolid treatment significantly inhibited cell proliferation, migration and invasion in vitro. The epithelial–mesenchymal transition (EMT) was impaired by haprolid treatment and the expression level of N-cadherin, vimentin and Snail was downregulated. Moreover, growth of HCC cells in vitro was suppressed by inhibition of G1/S transition, and partially by induction of apoptosis. The drug induced downregulation of cell cycle regulatory proteins cyclin A, cyclin B and CDK2 and induced upregulation of p21 and p27. Further evidence showed that these effects of haprolid were associated with Rb/E2F downregulation and Akt/mTOR inhibition. Finally, in vivo nude mice experiments demonstrated significant inhibition of tumor growth upon haprolid treatment. Conclusion: Our results show that haprolid inhibits the growth of HCC through dual inhibition of Rb/E2F and Akt/mTOR pathways. Therefore, haprolid might be considered as a new and promising candidate for the palliative therapy of HCC.

scholarly journals NFATc1 Promotes Epithelial-Mesenchymal Transition and Facilitates Colorectal Cancer Metastasis by Targeting SNAI1

2020 ◽  
Author(s):  
Tianli Shen ◽  
Chenyang Yue ◽  
Xingjie Wang ◽  
Zijun Wang ◽  
Yunhua Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Activated T Cells ◽  
In Vivo Models ◽  
Mesenchymal Transition ◽  
Clinical Stages

Abstract BackgroundMetastatic recurrence remains a major cause of colorectal cancer (CRC) mortality. In this study, we focused on the role and the potential underlying mechanisms of nuclear factor of activated T cells 1 (NFATc1) in CRC metastasis. MethodsWe examined the expression of NFATc1 in 140 cases of CRC tissues and 35 corresponding adjacent tissues, as well as analyzed the correlation between NFATc1 expression levels and clinical stages. The role of NFATc1 in CRC metastasis and the molecular mechanisms were investigated in both in vitro and in vivo models. ResultsThe results showed that NFATc1 expression was increased in metastatic CRC tissues and positively associated with clinical stages (Stage I vs. Stage II, III or IV) of CRC. Overexpression of NFATc1 promoted CRC cell migration, invasion and epithelial-mesenchymal transition (EMT). Moreover, SNAI1 was verified as the direct transcriptional target of NFATc1 and interacted with Slug to promote EMT. Remarkably, our lung and liver double metastasis mouse model demonstrated that NFATc1 overexpression accelerated CRC metastasis, and treatment with FK506, a calcineurin-NFAT pathway inhibitor, could suppress CRC metastasis in vivo. ConclusionsTaken together, our findings suggest that NFATc1 could transcriptionally activate SNAI1, which in turn could interact with Slug to mediate EMT and to promote CRC metastasis, making NFATc1 a promising target in CRC treatment.

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