LncRNA XIST/miR-137 axis strengthens chemo-resistance and glycolysis of colorectal cancer cells by hindering transformation from PKM2 to PKM1

2020 ◽  
pp. 1-12
Author(s):  
Hailun Zheng ◽  
Mei Zhang ◽  
Xiquan Ke ◽  
Xiaojing Deng ◽  
Dapeng Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cisplatin Resistance ◽  
Extracellular Acidification ◽  
Normal Tissues ◽  
Enhanced Sensitivity ◽  
Tumor Tissues ◽  
Glycolytic Potential ◽  
Colorectal Cancer Cells ◽  
Epithelial Cell Lines ◽  
Lncrna Xist

BACKGROUND: Glycolysis was an essential driver of chemo-resistance in colorectal cancer (CRC), albeit with limited molecular explanations. OBJECTIVE: We strived to elucidate the involvement of lncRNA XIST/miR-137/PKM axis in chemo-tolerance and glycolysis of CRC. METHODS: Altogether 212 pairs of tumor tissues and adjacent normal tissues were collected from CRC patients. Moreover, human CRC epithelial cell lines, including HT29, SW480, SW620 and LoVo, were purchased in advance, and their activity was estimated after transfection of si-XIST or miR-137 mimic. Furthermore, 5-FU/cisplatin-resistance of CRC cells was determined through MTT assay, and glycolytic potential of CRC cells was appraised based on oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). RESULTS: Highly-expressed XIST were predictive of severe symptoms and unfavorable 3-year survival of CRC patients (P< 0.05). Besides, silencing of XIST not only diminished proliferative, migratory and invasive power of CRC cells (P< 0.05), but also enhanced sensitivity of CRC cells responding to 5-FU/cisplatin (P< 0.05). Glycolytic potency of CRC cells was also undermined by si-XIST, with decreased maximal respiration and maximal glycolytic capacity in the si-XIST group as relative to NC group (P< 0.05). Nevertheless, miR-137 mimic attenuated the facilitating effect of pcDNA3.1-XIST on proliferation, migration, invasion, 5-FU/cisplatin-resistance and glycolysis of CRC cells (P< 0.05). Ultimately, ratio of PKM2 mRNA and PKM1 mRNA, despite being up-regulated by pcDNA3.1-XIST, was markedly lowered when miR-137 mimic was co-transfected (P< 0.05). CONCLUSIONS: LncRNA XIST/miR-137 axis reinforced glycolysis and chemo-tolerance of CRC by elevating PKM2/PKM1 ratio, providing an alternative to boost chemo-therapeutic efficacy of CRC patients.

scholarly journals Effect of KNL1 on the proliferation and apoptosis of colorectal cancer cells

2019 ◽  
Vol 18 ◽  
pp. 153303381985866 ◽  
Author(s):  
Tianliang Bai ◽  
Yalei Zhao ◽  
Yabin Liu ◽  
Bindan Cai ◽  
Ning Dong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Protein Expression ◽  
Cancer Cells ◽  
Tumor Location ◽  
Colorectal Tumor ◽  
Infiltration Depth ◽  
Normal Tissues ◽  
Tumor Tissues ◽  
Colorectal Cancer Cells ◽  
Cancer Tissues

Objective: To identify the expression of kinetochore scaffold 1 ( KNL1) in colorectal tumor tissues and to clarify the role of this gene in the proliferation capability of colorectal cancer cells. Methods: A total of 108 paired colorectal tumor and normal tissue samples were collected from patients with colorectal cancer and subjected to quantitative polymerase chain reaction and immunohistochemistry analyses. Expression levels of KNL1 mRNA and protein were compared between tumor and normal tissues, and KNL1 levels were evaluated in relation to the patients’ tumor differentiation, sex, lymph node metastasis, TNM stage, infiltration depth, age, and tumor location. Survival curves were also constructed and compared between patients with tumor samples with and without KLN1 protein expression. KNL1 was under-expressed in colorectal cancer cells in vitro using lentiviral transfection with short hairpin RNA, and its function was evaluated by proliferation, colony-formation, and apoptosis assays. Expression levels of BUB1 protein were also compared between tumor and normal tissues, and the correlation between KNL1 expression and BUB1 expression in colorectal cancer tissues was examined. Results: KNL1 mRNA and protein were both highly expressed in colorectal tumor tissues compared with paired normal tissues. KNL1 downregulation significantly inhibited colorectal cancer cell proliferation and colony formation, and promoted apoptosis. KNL1 protein expression was significantly associated with tumor differentiation, but not with sex, lymph node metastasis, TNM stage, infiltration depth, age, or tumor location. KNL1 protein expression was also significantly associated with poorer survival. Moreover, there was a significant correlation between KNL1 and BUB1 in colorectal cancer tissues. Conclusions: KNL1 plays an effective role in decreasing apoptosis and promoting the proliferation of colorectal cancer cells, suggesting that its inhibition may represent a promising therapeutic approach in patients with colorectal cancer.

Some characteristics of cancer-testis gene expression regulation in colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14233-e14233
Author(s):  
Kristina I. Soldatova ◽  
Oleg Ivanovich Kit ◽  
Roman E. Tolmakh ◽  
Denis S. Kutilin
Keyword(s):  
Colorectal Cancer ◽  
Cluster Analysis ◽  
Copy Number ◽  
Dna Methyltransferase ◽  
Gene Expression Regulation ◽  
Strong Positive Correlation ◽  
Aberrant Expression ◽  
Normal Tissues ◽  
Tumor Tissues ◽  
Cancer Testis

e14233 Background: Cancer-testis antigens (CTA) can be used in immunotherapy and for early detection of cancer. Despite numerous studies of the CTA expression in different tumors, their transcriptional activity and its regulation in colorectal cancer (CRC) remain poorly understood. The purpose of the study was to analyze the expression of cancer-testis genes (CT-genes) and mechanisms of its regulation in CRC. Methods: Tumor and intact tissues of the colon were studied in 60 patients. RNAs were isolated using the method described by Chomczynski and Sacchi (2006). The REVERTA-L reagent kit was used for the cDNA synthesis. Expression of 16 CT-genes (MAGE-A1, -A2, -A3, -A4, MAGE-B1, -B2, GAGE-1, -3, -4, MAGEC1, BAGE, XAGE3, NYESO1, SSX2, SCP1, PRAME1) and expression and copy number of 3 DNA methyltransferase genes (DNMT1, DNMT3A, DNMT3B) were determined by Real-Time qPCR (GAPDH and GUSB - reference genes). For the cluster analysis, we used our R scripts. Differences were assessed by the Mann-Whitney test, and correlations – by the Spearman's rank correlation coefficient (r). Results: The expression of 2 CT genes, SSX2 and PRAME1, was increased (p < 0.05) by 1.8 and 2.9 times, respectively, and the BAGE expression was decreased by 2.4 times in tumor tissues, compared to the normal tissues. The expression and copy number of DNMT3A in tumor tissues was 1.5 and 2 times higher (p < 0.05), and that of DNMT3B – 2 times lower (p < 0.005), compared to normal tissues. The copy number and expression of the DNMT1 gene did not change. A strong positive correlation (r = 0.996) between the expression and copy number of DNA methyltransferase genes was observed. Using cluster analysis (Hierarchical Clustering, Euclidean distance), we detected two clusters of CRC samples different in the expression of CT-genes and methyltransferases. Cluster 1 showed increased expression of DNMT1, DNMT3A and DNMT3B and decreased expression of BAGE, SSX2 and PRAME1; cluster 2 – decreased expression of DNMT1, DNMT3A and DNMT3B and increased expression of BAGE, SSX2 and PRAME1. Conclusions: The detected aberrant expression of the CT-genes BAGE, SSX2, PRAME1 in CRC depends on the expression of DNMT1, DNMT3A, DNMT3B, which in its turn depends on the copy number of the corresponding DNA methyltransferase genes.

scholarly journals ANRIL promotes chemoresistance via disturbing expression of ABCC1 by regulating the expression of Let-7a in colorectal cancer

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Zhen Zhang ◽  
Lifeng Feng ◽  
Pengfei Liu ◽  
Wei Duan
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Clinical Prognosis ◽  
Normal Tissues ◽  
Kaplan Meier ◽  
Non Coding Rna ◽  
Tumor Tissues ◽  
Oncogenic Gene ◽  
Poor Clinical Prognosis

Increasing evidence indicates that long non-coding RNAs (lncRNAs) antisense non-coding RNA in the INK4 locus (ANRIL) has been involved in various diseases and promotes tumorigenesis and cancer progression as an oncogenic gene. However, the effect of ANRIL on chemoresistance remains still unknown in colorectal cancer (CRC). Here, we investigated ANRIL expression in 63 cases of colorectal cancer specimens and matched normal tissues. Results revealed that ANRIL was up-regulated in tumor tissues samples from patients with CRC and CRC cell lines. Increased ANRIL expression in CRC was associated with poor clinical prognosis. Kaplan–Meier analysis showed that ANRIL was associated with overall survival of patients with colorectal cancer, and patients with high ANRIL expression tended to have unfavorable outcome. In vitro experiments revealed that ANRIL knockdown significantly inhibited CRC cell proliferation, improved the sensitivity of chemotherapy and promoted apoptosis. Further functional assays indicated that ANRIL overexpression significantly promoted cell chemoresistance by regulating ATP-binding cassette subfamily C member 1 through binding Let-7a. Taken together, our study demonstrates that ANRIL could act as a functional oncogene in CRC, as well as a potential therapeutic target to inhibit CRC chemoresistance.

scholarly journals miR-20a regulates sensitivity of colorectal cancer cells to NK cells by targeting MICA

2019 ◽  
Vol 39 (7) ◽  
Author(s):  
Siwen Tang ◽  
Hongyu Fu ◽  
Qihua Xu ◽  
Ying Zhou
Keyword(s):  
Colorectal Cancer ◽  
Nk Cells ◽  
Luciferase Reporter ◽  
Normal Tissues ◽  
Histocompatibility Complex ◽  
Colorectal Cancer Cells ◽  
Reporter Assays ◽  
Direct Target ◽  
Causes Of Deaths

Abstract Colorectal cancer (CRC) is one of the leading cancer-related causes of deaths in the world. Recently, microRNAs have been reported to regulate the tumor growth, invasion and the immunosuppression. In the present study, we found that miR-20a was increased in human CRC specimens compared with the healthy normal tissues. However, miR-20a overexpression and knockdown did not impair the CRC cell growth in vitro. Our results indicated that CD107a+ NK cells are increased in CRC group. Furthermore, cytotoxicity assays demonstrated that miR-20a knockdown promoted the CRC cells sensitive to NK cells, whereas miR-20a overexpression showed the opposite results. Our results suggest that the regulation of NK cells by miR-20a depends on NKG2D. Luciferase reporter assays revealed that the NKG2D ligand Major Histocompatibility Complex (MHC) class I-related chain genes A (MICA) is the direct target of miR-20a. Flow cytometry showed the MICA protein level is significantly reduced in miR-20a-overexpressing CRC cells and increased in miR-20a knockdown CRC cells. Taken together, our results suggest that miR-20a regulates sensitivity of CRC cells to NK cells by targeting MICA.

scholarly journals TRIM39 deficiency inhibits tumor progression and autophagic flux in colorectal cancer via suppressing the activity of Rab7

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Jia Hu ◽  
Xueliang Ding ◽  
Shaobo Tian ◽  
Yanan Chu ◽  
Zhibo Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Autophagic Flux ◽  
Dependent Manner ◽  
Functional Studies ◽  
Normal Tissues ◽  
Tumor Tissues ◽  
Autophagic Degradation ◽  
Activity Dependent

AbstractThe biological function of TRIM39, a member of TRIM family, remains largely unexplored in cancer, especially in colorectal cancer (CRC). In this study, we show that TRIM39 is upregulated in tumor tissues compared to adjacent normal tissues and associated with poor prognosis in CRC. Functional studies demonstrate that TRIM39 deficiency restrains CRC progression in vitro and in vivo. Our results further find that TRIM39 is a positive regulator of autophagosome–lysosome fusion. Mechanistically, TRIM39 interacts with Rab7 and promotes its activity via inhibiting its ubiquitination at lysine 191 residue. Depletion of TRIM39 inhibits CRC progression and autophagic flux in a Rab7 activity-dependent manner. Moreover, TRIM39 deficiency suppresses CRC progression through inhibiting autophagic degradation of p53. Thus, our findings uncover the roles as well as the relevant mechanisms of TRIM39 in CRC and establish a functional relationship between autophagy and CRC progression, which may provide promising approaches for the treatment of CRC.

scholarly journals Analysis of changes in microbiome compositions related to the prognosis of colorectal cancer patients based on tissue-derived 16S rRNA sequences

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Sukjung Choi ◽  
Jongsuk Chung ◽  
Mi-La Cho ◽  
Donghyun Park ◽  
Sun Shim Choi
Keyword(s):  
Colorectal Cancer ◽  
16S Rrna ◽  
Pathogenic Bacteria ◽  
Fusobacterium Nucleatum ◽  
Amplicon Sequencing ◽  
Normal Tissues ◽  
16S Rrna Amplicon Sequencing ◽  
Tumor Tissues ◽  
Colorectal Cancer Patients ◽  
Host Genes

Abstract Background Comparing the microbiome compositions obtained under different physiological conditions has frequently been attempted in recent years to understand the functional influence of microbiomes in the occurrence of various human diseases. Methods In the present work, we analyzed 102 microbiome datasets containing tumor- and normal tissue-derived microbiomes obtained from a total of 51 Korean colorectal cancer (CRC) patients using 16S rRNA amplicon sequencing. Two types of comparisons were used: ‘normal versus (vs.) tumor’ comparison and ‘recurrent vs. nonrecurrent’ comparison, for which the prognosis of patients was retrospectively determined. Results As a result, we observed that in the ‘normal vs. tumor’ comparison, three phyla, Firmicutes, Actinobacteria, and Bacteroidetes, were more abundant in normal tissues, whereas some pathogenic bacteria, including Fusobacterium nucleatum and Bacteroides fragilis, were more abundant in tumor tissues. We also found that bacteria with metabolic pathways related to the production of bacterial motility proteins or bile acid secretion were more enriched in tumor tissues. In addition, the amount of these two pathogenic bacteria was positively correlated with the expression levels of host genes involved in the cell cycle and cell proliferation, confirming the association of microbiomes with tumorigenic pathway genes in the host. Surprisingly, in the ‘recurrent vs. nonrecurrent’ comparison, we observed that these two pathogenic bacteria were more abundant in the patients without recurrence than in the patients with recurrence. The same conclusion was drawn in the analysis of both normal and tumor-derived microbiomes. Conclusions Taken together, it seems that understanding the composition of tissue microbiomes is useful for predicting the prognosis of CRC patients.

scholarly journals Cytotoxic T-Cell Trafficking Chemokine Profiles Correlate With Defined Mucosal Microbial Communities in Colorectal Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiali Zhang ◽  
Ji Tao ◽  
Ruo-Nan Gao ◽  
Zhi-Yuan Wei ◽  
Yu-Shan He ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Gut Microbiota ◽  
Oral Bacteria ◽  
Cytotoxic T Cell ◽  
Cell Trafficking ◽  
Gut Microbes ◽  
T Cell Trafficking ◽  
Normal Tissues ◽  
Tumor Tissues

The involvement of gut microbiota in T-cell trafficking into tumor tissue of colorectal cancer (CRC) remains to be further elucidated. The current study aimed to evaluate the expression of major cytotoxic T-cell trafficking chemokines (CTTCs) and chemokine-associated microbiota profiles in both tumor and adjacent normal tissues during CRC progression. We analyzed the expression of chemokine C-X-C motif ligands 9, 10, and 11 (CXCL9, CXCL10, and CXCL11), and C-C motif ligand 5 (CCL5), characterized gut mucosa-associated microbiota (MAM), and investigated their correlations in CRC patients. Our results showed that the expression of CXCL9, CXCL10, and CXCL11 was significantly higher in tumor than in adjacent normal tissues in 136 CRC patients. Notably, the high expression of CXCL9 in tumor tissues was associated with enhanced CD8+ T-cell infiltration and improved survival. Moreover, the MAM in tumor tissues showed reduction of microbial diversity and increase of oral bacteria. Microbial network analysis identified differences in microbial composition and structure between tumor and adjacent normal tissues. In addition, stronger associations between oral bacteria and other gut microbes were observed. Furthermore, the correlation analysis between the defined MAM and individual CTTCs showed that the CTTCs’ correlated operational taxonomic units (OTUs) in tumor and adjacent normal tissues rarely overlap with each other. Notably, all the enriched OTUs were positively correlated with the CTTCs in either tumor or adjacent normal tissues. Our findings demonstrated stronger interactions between oral bacteria and gut microbes, and a shifted correlation pattern between MAM and major CTTCs in tumor tissues, underlining possible mechanisms of gut microbiota–host interaction in CRC.

Assessing the Chemosensitizing Effect of Neferine on Cisplatin-Resistant Colorectal Cancer Cells through Molecular Docking Studies

2021 ◽  
pp. 33-44
Author(s):  
S. Bharath ◽  
S. Gopinath ◽  
S. Surovi ◽  
V. Vijaya Padma
Keyword(s):  
Colorectal Cancer ◽  
Molecular Docking ◽  
Growth Factor ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Docking Studies ◽  
Cell Surface Receptor ◽  
Multi Drug Resistance ◽  
Target Proteins ◽  
Colorectal Cancer Cells

Colorectal cancer (CRC) is the second deadliest diseases next to lung cancer. Cisplatin is the first generation platinum based alkylating agent using for treatment of advance CRC patients. Continuous usages of cisplatin lead to resistance which limits its therapeutic efficacy. Recent research is focused on studying the chemotherapeutic efficacy of the phytochemicals as they are less toxic compared to the conventional chemotherapeutic drugs. Neferine is a bisbenzylisoquinoline alkaloid extracted from the embryo of Nelumbo nucifera. The anticancer and chemosensitizing effect of neferine has been well reported in several cancer cells. However, there are no reports on the chemosensitizing effect of neferine on cisplatin-resistant colorectal cancer cells (CRCs). Hence, the present study aims at identification of target proteins responsible for cisplatin-resistance in colorectal cancer cells. The present investigation elucidates the specific interaction of neferine with various cell surface receptor proteins related to cisplatin-resistance, multi-drug resistance (MDR) proteins, signal transduction protein and transcription factors via molecular docking approach. The interaction between neferine and the target proteins of cisplatin-resistant colorectal cancer was analyzed through Schrodinger Maestro 11.9 module. From our docking studies we could suggest that neferine is most active for insulin-like growth factor-1 receptor (IGF1R), fibroblast growth factor receptor-2 (FGFR2), zinc finger protein SNAI1 (SNAIL1), signal transducer and activator of transcription-3 (STAT3) and transforming growth factor beta receptor-1 (TGFβR1) when sorted according to their docking score.

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