scholarly journals Identification of PTPLAD1 as a Novel Tumor Suppressor and its Implication in Metastatic Colon Cancer Therapy

2021 ◽  
Author(s):  
Jie Yang ◽  
Yangjia Li ◽  
Yang Hu ◽  
Weixia Zhang ◽  
Xin Yan ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Therapy ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Cancer Metastasis ◽  
Signaling Cascades ◽  
Boyden Chamber ◽  
Metastatic Colon Cancer ◽  
Colon Cancer Metastasis ◽  
Targeted Drug

Abstract Background: Colon cancer is one of the most common malignant cancers, and cancer metastasis always leads to a failure of clinical treatment. Although there have been many studies on the process of colon cancer progression, the detailed mechanism of colon cancer metastasis still remains unclear, and more effective drugs targeting colon cancer metastasis are urgently needed. This study aims to explore novel effectors involved in colon cancer metastasis and screen out potential targeted drug for colon cancer therapy.Methods: Mass spectrometry and bioinformatics analyses are performed to present the proteomics variation between two colon cancer cell lines with different invasion abilities. Boyden chamber invasion assay (in vitro) and experimental metastasis assay in mice (in vivo) are performed to explore the role of protein tyrosine phosphatase-like A domain containing 1 (PTPLAD1) in colon cancer metastasis. Western blotting and qRT-PCR assays are performed to analyze the expression of proteins and mRNA of related signaling cascades. Co-immunoprecipitation (Co-IP) and confocal assays are conducted to examine the proteins interacted with PTPLAD1. Chromatin-immunoprecipitation (ChIP) assay is fulfilled to evaluate the relationship of PTPLAD1 expression and histone H3K9 acetylation. Enzyme-linked immuno sorbent assay (ELISA) screening system are used to screen out the small molecular inhibitor that mimics the effect of PTPLAD1 on suppressing colon cancer metastasis.Results: Our results identify that PTPLAD1 is significantly downregulated in the highly invasive cell lines, and PTPLAD1 suppresses colon cancer metastasis by interacting with prohibitin (PHB) and prohibiting the activation of PHB/C-Raf1 (Raf)/ extracellular signal-regulated kinase (ERK)/Snail signaling pathway. Moreover, the expression of PTPLAD1 is modulated through the acetylation of histone H3K9. Besides, we identify a small molecule named avobenzone, once used to protect skin from ultraviolet damage, that can disrupt the interaction of PHB and Raf, significantly abrogate the activation of downstream signaling cascades and prohibit colon cancer metastasis.Conclusions: Collectively, our study not only identifies PTPLAD1 as a novel tumor suppressor and clarifies its role in suppressing colon cancer metastasis, but also provides a potential targeted drug for metastatic colon cancer therapy.

scholarly journals Exosomal lncRNA PVT1/VEGFA Axis Promotes Colon Cancer Metastasis and Stemness by Downregulation of Tumor Suppressor miR-152-3p

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Shiue-Wei Lai ◽  
Ming-Yao Chen ◽  
Oluwaseun Adebayo Bamodu ◽  
Ming-Shou Hsieh ◽  
Ting-Yi Huang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Growth Factor ◽  
Cell Lines ◽  
Distant Metastasis ◽  
Cancer Metastasis ◽  
Lovo Cell ◽  
Promoting Effect ◽  
Colon Cancer Metastasis

Background. Treating advanced colon cancer remains challenging in clinical settings because of the development of drug resistance and distant metastasis. Mechanisms underlying the metastasis of colon cancer are complex and unclear. Methods. Computational analysis was performed to determine genes associated with the exosomal long noncoding (lncRNA) plasmacytoma variant translocation 1 (PVT1)/vascular endothelial growth factor A (VEGFA) axis in patients with colon cancer. The biological importance of the exosomal lncRNA PVT1/VEGFA axis was examined in vitro by using HCT116 and LoVo cell lines and in vivo by using a patient-derived xenograft (PDX) mouse model through knockdown (by silencing of PVT1) and overexpression (by adding serum exosomes isolated from patients with distant metastasis (M-exo)). Results. The in silico analysis demonstrated that PVT1 overexpression was associated with poor prognosis and increased expression of metastatic markers such as VEGFA and epidermal growth factor receptor (EGFR). This finding was further validated in a small cohort of patients with colon cancer in whom increased PVT1 expression was correlated with colon cancer incidence, disease recurrence, and distant metastasis. M-exo were enriched with PVT1 and VEGFA, and both migratory and invasive abilities of colon cancer cell lines increased when they were cocultured with M-exo. The metastasis-promoting effect was accompanied by increased expression of Twist1, vimentin, and MMP2. M-exo promoted metastasis in PDX mice. In vitro silencing of PVT1 reduced colon tumorigenic properties including migratory, invasive, colony forming, and tumorsphere generation abilities. Further analysis revealed that PVT1, VEGFA, and EGFR interact with and are regulated by miR-152-3p. Increased miR-152-3p expression reduced tumorigenesis, where increased tumorigenesis was observed when miR-152-3p expression was downregulated. Conclusion. Exosomal PVT1 promotes colon cancer metastasis through its association with EGFR and VEGFA expression. miR-152-3p targets both PVT1 and VEGFA, and this regulatory pathway can be explored for drug development and as a prognostic biomarker.

scholarly journals MicroRNAs as Regulator of Signaling Networks in Metastatic Colon Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Jian Wang ◽  
Yong Du ◽  
Xiaoming Liu ◽  
William C. Cho ◽  
Yinxue Yang
Keyword(s):  
Colon Cancer ◽  
Noncoding Rna ◽  
Cancer Metastasis ◽  
Target Genes ◽  
Signaling Networks ◽  
Metastatic Colon Cancer ◽  
Rna Molecules ◽  
Small Noncoding Rna ◽  
P53 Signaling ◽  
Colon Cancer Metastasis

MicroRNAs (miRNAs) are a class of small, noncoding RNA molecules capable of regulating gene expression translationally and/or transcriptionally. A large number of evidence have demonstrated that miRNAs have a functional role in both physiological and pathological processes by regulating the expression of their target genes. Recently, the functionalities of miRNAs in the initiation, progression, angiogenesis, metastasis, and chemoresistance of tumors have gained increasing attentions. Particularly, the alteration of miRNA profiles has been correlated with the transformation and metastasis of various cancers, including colon cancer. This paper reports the latest findings on miRNAs involved in different signaling networks leading to colon cancer metastasis, mainly focusing on miRNA profiling and their roles in PTEN/PI3K, EGFR, TGFβ, and p53 signaling pathways of metastatic colon cancer. The potential of miRNAs used as biomarkers in the diagnosis, prognosis, and therapeutic targets in colon cancer is also discussed.

scholarly journals Cytotoxicity and Apoptosis Effects of Curcumin Analogue (2E,6E)-2,6-Bis(2,3-Dimethoxybenzylidine) Cyclohexanone (DMCH) on Human Colon Cancer Cells HT29 and SW620 In Vitro

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1261
Author(s):  
Nurul Fattin Che Rahim ◽  
Yazmin Hussin ◽  
Muhammad Nazirul Mubin Aziz ◽  
Nurul Elyani Mohamad ◽  
Swee Keong Yeap ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Lines ◽  
Curcuma Longa ◽  
Metastatic Colon Cancer ◽  
Colon Cancer Cells ◽  
Human Colon Cancer ◽  
Sw620 Cell

Colorectal cancer (CRC) is the third most common type of cancer worldwide and a leading cause of cancer death. According to the Malaysian National Cancer Registry Report 2012–2016, colorectal cancer was the second most common cancer in Malaysia after breast cancer. Recent treatments for colon cancer cases have caused side effects and recurrence in patients. One of the alternative ways to fight cancer is by using natural products. Curcumin is a compound of the rhizomes of Curcuma longa that possesses a broad range of pharmacological activities. Curcumin has been studied for decades but due to its low bioavailability, its usage as a therapeutic agent has been compromised. This has led to the development of a chemically synthesized curcuminoid analogue, (2E,6E)-2,6-bis(2,3-dimethoxybenzylidine) cyclohexanone (DMCH), to overcome the drawbacks. This study aims to examine the potential of DMCH for cytotoxicity, apoptosis induction, and activation of apoptosis-related proteins on the colon cancer cell lines HT29 and SW620. The cytotoxic activity of DMCH was evaluated using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) cell viability assay on both of the cell lines, HT29 and SW620. To determine the mode of cell death, an acridine orange/propidium iodide (AO/PI) assay was conducted, followed by Annexin V/FITC, cell cycle analysis, and JC-1 assay using a flow cytometer. A proteome profiler angiogenesis assay was conducted to determine the protein expression. The inhibitory concentration (IC50) of DMCH in SW620 and HT29 was 7.50 ± 1.19 and 9.80 ± 0.55 µg/mL, respectively. The treated cells displayed morphological features characteristic of apoptosis. The flow cytometry analysis confirmed that DMCH induced apoptosis as shown by an increase in the sub-G0/G1 population and an increase in the early apoptosis and late apoptosis populations compared with untreated cells. A higher number of apoptotic cells were observed on treated SW620 cells as compared to HT29 cells. Human apoptosis proteome profiler analysis revealed upregulation of Bax and Bad proteins and downregulation of Livin proteins in both the HT29 and SW620 cell lines. Collectively, DMCH induced cell death via apoptosis, and the effect was more pronounced on SW620 metastatic colon cancer cells, suggesting its potential effects as an antimetastatic agent targeting colon cancer cells.

scholarly journals Colon cancer metastasis to the lateral skull base masquerading as mastoiditis

2019 ◽  
Vol 13 ◽  
pp. 100126
Author(s):  
Nathan R. Lindquist ◽  
David C. Wilde ◽  
Eric N. Appelbaum ◽  
Edward A. Duckworth ◽  
Alex D. Sweeney
Keyword(s):  
Colon Cancer ◽  
Skull Base ◽  
Cancer Metastasis ◽  
Colon Cancer Metastasis ◽  
Lateral Skull Base
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