MicroRNAs as Regulator of Signaling Networks in Metastatic Colon Cancer

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.

Download Full-text

MicroRNAs in endometriosis: biological function and emerging biomarker candidates†

Biology of Reproduction ◽

10.1093/biolre/ioz014 ◽

2019 ◽

Vol 101 (6) ◽

pp. 1167-1178 ◽

Cited By ~ 6

Author(s):

Sarah Bjorkman ◽

Hugh S Taylor

Keyword(s):

Noncoding Rna ◽

Target Genes ◽

Biological Function ◽

Transcriptional Regulators ◽

Circulating Mirnas ◽

Common Chronic Disease ◽

Rna Molecules ◽

Small Noncoding Rna ◽

Reproductive Aged Women ◽

Delayed Time

AbstractMicroRNAs (miRNAs), a class of small noncoding RNA molecules, have been recognized as key post-transcriptional regulators associated with a multitude of human diseases. Global expression profiling studies have uncovered hundreds of miRNAs that are dysregulated in several diseases, and yielded many candidate biomarkers. This review will focus on miRNAs in endometriosis, a common chronic disease affecting nearly 10% of reproductive-aged women, which can cause pelvic pain, infertility, and a myriad of other symptoms. Endometriosis has delayed time to diagnosis when compared to other chronic diseases, as there is no current accurate, easily accessible, and noninvasive tool for diagnosis. Specific miRNAs have been identified as potential biomarkers for this disease in multiple studies. These and other miRNAs have been linked to target genes and functional pathways in disease-specific pathophysiology. Highlighting investigations into the roles of tissue and circulating miRNAs in endometriosis, published through June 2018, this review summarizes new connections between miRNA expression and the pathophysiology of endometriosis, including impacts on fertility. Future applications of miRNA biomarkers for precision medicine in diagnosing and managing endometriosis treatment are also discussed.

Download Full-text

Long Noncoding RNA ASLNC07322 Functions in VEGF-C Expression Regulated by Smad4 during Colon Cancer Metastasis

Molecular Therapy — Nucleic Acids ◽

10.1016/j.omtn.2019.10.012 ◽

2019 ◽

Vol 18 ◽

pp. 851-862 ◽

Cited By ~ 3

Author(s):

Xuemei Li ◽

Xiaohong Lv ◽

Zhuowei Li ◽

Chao Li ◽

Xinlei Li ◽

...

Keyword(s):

Colon Cancer ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Cancer Metastasis ◽

Colon Cancer Metastasis

Download Full-text

Investigation and Identification of let-7a Related Functional Proteins in Gastric Carcinoma by Proteomics

Analytical Cellular Pathology ◽

10.1155/2012/691218 ◽

2012 ◽

Vol 35 (4) ◽

pp. 285-295 ◽

Cited By ~ 5

Author(s):

Yimin Zhu ◽

Xingyuan Xiao ◽

Lairong Dong ◽

Zhiming Liu

Keyword(s):

Gastric Carcinoma ◽

Noncoding Rna ◽

Target Genes ◽

Rho Gtpase ◽

Two Dimensional Gel Electrophoresis ◽

Gastric Carcinoma Cell ◽

Rna Molecules ◽

Small Noncoding Rna

MicroRNAs are small noncoding RNA molecules that control expression of target genes. Our previous studies show that let-7a decreased in gastric carcinoma and that up-regulation of let-7a by gene augmentation inhibited gastric carcinoma cell growth bothin vitroandin vivo, whereas it remains largely unclear as to how let-7a affects tumor growth. In this study, proteins associated with the function of let-7a were detected by high throughout screening. The cell line of SGC-7901 stablely overexpressing let-7a was successfully established by gene cloning. Two-dimensional gel electrophoresis (2-DEy was used to separate the total proteins of SGC-7901/let-7a, SGC-7901/EV and SGC-7901, and PDQuest software was applied to analyze 2-DE images. Ten different protein spots were identified by MALDI-TOF-MS, and they may be the proteins associated with let-7a function. The overexpressed proteins included Antioxidant protein 2, Insulin–like growth factor binding protein 2, Protein disulfide isomerase A2, C-1-tetrahydrofolate synthase, Cyclin-dependent kinase inhibitor1 (CDKN1) and Rho–GTPase activating protein 4. The underexpressed proteins consisted of S-phase kinase-associated protein 2 (Spk2), Platelet membrane glycoprotein, Fibronectin and Cks1 protein. Furthermore, the different expression levels of the partial proteins (CDKN1, Spk2 and Fibronectin) were confirmed by western blot analysis. The data suggest that these differential proteins are involved in a novel let-7a signal pathway and these findings provide the basis to investigate the functional mechanisms of let-7a in gastric carcinoma.

Download Full-text

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

10.21203/rs.3.rs-942066/v1 ◽

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.

Download Full-text

NSUN2-Mediated Splice Site m5C Methylation Modification Promotes the Progression of Colon Cancer Through Modulating the Discrepant Cleavage of tRNA-Arg

10.21203/rs.3.rs-786758/v1 ◽

2021 ◽

Author(s):

Na Luan ◽

Yanjing Cao ◽

Jianguo Sun ◽

Jiayi Mu ◽

Yali Mu ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Noncoding Rna ◽

Cancer Metastasis ◽

Tumour Progression ◽

Colon Cancer Cells ◽

Rna Methylation ◽

Tumour Metastasis ◽

Colon Cancer Metastasis

Abstract Background: Hypoxia is a key driving factor for the tumour microenvironment restructuring, which leading to the variation of gene expression profiling in cancer cells. Increasing evidence reveals the initial action of hypoxia in the epitranscriptomics including RNA methylation. The role of tRNA-derived fragments (tRFs) in regulating tumour metastasis potential has attracted attention. Methods: The expression of tRFs in colon cancer cells under hypoxia were evaluated based on full-transcript sequencing and bioinformatics analysis and their effects on colon cancer metastasis were detected by transwell assays. The role of C34 was verified by introducing mutation and artificial m5C modification. The effects of NSUN2 on the biological characteristics of colon cancer cells were investigated on the basis of gain-of-function and loss-of function analyses. Lung metastasis model further uncovered the roles of NSUN2 and key tRF in tumour progression. Assays of RNA immunoprecipitation-qPCR (RIP-qPCR) were performed to identify that NSUN2 is a key methyltransferase for cysteine modification at C34 of tRNA-Arg.Results: The present study verified the up-expression of tRF (tRF-20-MEJB5Y13) and down-expression of tRFs (tRF-20-M0NK5Y93 and tRF-21-3OPP6N7KE) in colon cancer cells under hypoxia, and all of them were derived from different tRNA-Arg. Contradictory effects of these three tRNA-Arg-derived tRFs on metastatic potential of colon cancer were demonstrated in this study. The sequence differences and the key nucleotide bases of tRNA with the methylation modification potential among the source tRNAs were analysed. Notably, our data identified C34 of tRNA-Arg as a key site that may play an important role in hypoxia-mediated tRNA-Arg discrepant cleavage. We further investigated that NSUN2 mediated specific site methylation of tRNA-Arg at C34, thereby protecting tRNA from cleavage by endonuclease and subsequently promoting the colon cancer metastasis both in vitro and in vivo. Conclusion: The present study elaborates on the precise regulatory mechanism of m5C methylation and the role in the selective cleavage of tRNA from the perspective of noncoding RNA methylation epitranscriptomics, providing a novel insight into the molecular basis of selective expression of tRFs in colon cancer under hypoxia.

Download Full-text