An Integrated Bioinformatics Analysis Repurposes an Antihelminthic Drug Niclosamide for Treating HMGA2-Overexpressing Human Colorectal Cancer

Aberrant overexpression of high mobility group AT-hook 2 (HMGA2) is frequently found in cancers and HMGA2 has been considered an anticancer therapeutic target. In this study, a pan-cancer genomics survey based on Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) data indicated that HMGA2 was mainly overexpressed in gastrointestinal cancers including colorectal cancer. Intriguingly, HMGA2 overexpression had no prognostic impacts on cancer patients’ overall and disease-free survivals. In addition, HMGA2-overexpressing colorectal cancer cell lines did not display higher susceptibility to a previously identified HMGA2 inhibitor (netroposin). By microarray profiling of HMGA2-driven gene signature and subsequent Connectivity Map (CMap) database mining, we identified that S100 calcium-binding protein A4 (S100A4) may be a druggable vulnerability for HMGA2-overexpressing colorectal cancer. A repurposing S100A4 inhibitor, niclosamide, was found to reverse the HMGA2-driven gene signature both in colorectal cancer cell lines and patients’ tissues. In vitro and in vivo experiments validated that HMGA2-overexpressing colorectal cancer cells were more sensitive to niclosamide. However, inhibition of S100A4 by siRNAs and other inhibitors was not sufficient to exert effects like niclosamide. Further RNA sequencing analysis identified that niclosamide inhibited more cell-cycle-related gene expression in HMGA2-overexpressing colorectal cancer cells, which may explain its selective anticancer effect. Together, our study repurposes an anthelminthic drug niclosamide for treating HMGA2-overexpression colorectal cancer.

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Surface-bound galectin-4 regulates gene transcription and secretion of chemokines in human colorectal cancer cell lines

Tumor Biology ◽

10.1177/1010428317691687 ◽

2017 ◽

Vol 39 (3) ◽

pp. 101042831769168 ◽

Cited By ~ 5

Author(s):

U Subrahmanyeswara Rao ◽

Prema S Rao

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Cell Surface ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Colorectal Cancer Cell ◽

Colorectal Tumorigenesis ◽

Colorectal Cancer Cells ◽

Colorectal Cancer Cell Lines

One long-term complication of chronic intestinal inflammation is the development of colorectal cancer. However, the mechanisms linking inflammation to the colorectal tumorigenesis are poorly defined. Previously, we have demonstrated that galectin-4 is predominantly expressed in the luminal epithelia of the gastrointestinal tract, and its loss of expression plays a key role in the colorectal tumorigenesis. However, the mechanism by which galectin-4 regulates inflammation-induced tumorigenesis is unclear. Here, we show that galectin-4 secreted by the colorectal cancer cell lines was bound to the cell surface. Neutralization of surface-bound galectin-4 with anti-galectin-4 antibody resulted in increased cell proliferation with concomitant secretion of several chemokines into the extracellular medium. Neutralization of the surface-bound galectin-4 also resulted in the up-regulation of transcription of 29 genes, several of which are components of multiple inflammation signaling pathways. In an alternate experiment, binding of recombinant galectin-4 protein to cell surface of the galectin-4-negative colorectal cancer cells resulted in increased p27, and decreased cyclin D1 and c-Myc levels, leading to cell cycle arrest and apoptosis. Together, these data demonstrated that surface-bound galectin-4 is a dual function protein—down-regulating cell proliferation and chemokine secretion in galectin-4-expressing colorectal cancer cells on one hand and inducing apoptosis in galectin-4-negative colorectal cancer cells on the other hand.

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HIPK3 Inhibition by Exosomal hsa-miR-101-3p Is Related to Metabolic Reprogramming in Colorectal Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.758336 ◽

2022 ◽

Vol 11 ◽

Author(s):

Lihuiping Tao ◽

Changliang Xu ◽

Weixing Shen ◽

Jiani Tan ◽

Liu Li ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Growth ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines ◽

Colorectal Cancer Cell ◽

Target Analysis ◽

Exosomal Mirnas ◽

Colorectal Cancer Cell Lines

BackgroundExosomes are extracellular vesicles secreted by most cells to deliver functional cargoes to recipient cells. MicroRNAs (miRNAs) constitute a significant part of exosomal contents. The ease of diffusion of exosomes renders them speedy and highly efficient vehicles to deliver functional molecules. Cancer cells secrete more exosomes than normal cells. Reports have showed that exosomal miRNAs of cancer cells facilitate cancer progression. Yet the complexity of cancer dictates that many more functional exosomal miRNAs remain to be discovered.MethodsIn this study, we analyzed miRNA expression profiles of tissue and plasma exosome samples collected from 10 colorectal cancer (CRC) patients and 10 healthy individuals. We focused on hsa-miR-101-3p (101-3p), a profoundly up-regulated miRNA enriched in plasma exosomes of patients bearing CRC. We performed target analysis of 101-3p and pursued functional studies of this microRNA in two colorectal cancer cell lines, namely HCT116 and SW480.ResultsOur results indicated that inhibiting 101-3p slowed cell growth and retarded cell migration in vivo in two colorectal cancer cell lines. Target analysis showed that Homeodomain-interacting protein kinase (HIPK3) is a target of miR-101-3p. HCT116 and SW480 cells stably overexpressing HIPK3 showed increased level of phosphorylated FADD, as well as retarded cell growth, migration, and increased sensitivity to 5-FU. In-depth analysis revealed increased mitochondrial membrane potential upon HIPK3 overexpression along with increased production of reactive oxygen species, number of mitochondria, and expression of respiratory complexes. Measurements of glycolytic parameters and enzymes revealed decreased level of glycolysis upon HIPK3 overexpression in these two cell lines. Xenograft model further confirmed a profoundly improved potency of the synergistic treatment combining both 5-FU and 101-3p inhibitor compared to 5-FU alone.ConclusionThis study unraveled an oncogenic nature of the exosomal 101-3p and suggested a relationship between the 101-3p-HIPK3 axis and metabolic homeostasis in colorectal cancer. Expression level of 101-3p is positively correlated with glycolytic capacity in CRC and therefore 101-3p itself is an oncomiR. Combining 101-3p inhibitor with chemotherapeutic agents is an effective strategy against CRC.

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Omentin-1 Promotes the Proliferation, Invasion, Migration and Angiogenesis of Colorectal Cancer Cells

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2019.2029 ◽

2019 ◽

Vol 9 (5) ◽

pp. 673-678

Author(s):

Hua Ye ◽

Hui Luo ◽

Yun Tu ◽

Liao Cui

Keyword(s):

Colorectal Cancer ◽

Western Blot ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Blot Analysis ◽

Western Blot Analysis ◽

Colorectal Cancer Cell ◽

Colorectal Cancer Cells ◽

Colorectal Cancer Cell Lines

Colorectal cancer (CRC) is one of the common malignant tumors of digestive system, which the incidence of CRC has been on the rise in recent years. Omentin-1 is reported to be increased in plasma of CRC patients. The present study aimed to investigate whether Omentin-1 could promote the proliferation, invasion, migration and angiogenesis of colorectal cancer cells. ELISA assay and western blot analysis detected the Omentin-1 level in plasma of CRC patients and western blot analysis and RT-qPCR analysis detected the Omentin-1 level in colorectal cancer cell lines. The transfection effects were verified by western blot analysis. The cell proliferation, invasion and migration were determined by CCK-8 assay, wound healing assay and transwell assay. The expression of MMP2, MMP9, VEGF and AngII was analyzed by western blot analysis. The results showed that Omentin-1 was increased in plasma of CRC patients and colorectal cancer cell lines. Omentin-1 overexpression promoted the proliferation, invasion, migration and angiogenesis of colorectal cancer cells. And, up-regulation of Omentin-1 increased the expression of MMP2, MMP9, VEGF and AngII. In conclusion, our data suggested that Omentin-1 promoted the proliferation, invasion, migration and angiogenesis of colorectal cancer cells.

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RAS specific protease induces irreversible growth arrest via p27 in several KRAS mutant colorectal cancer cell lines

Scientific Reports ◽

10.1038/s41598-021-97422-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Caleb K. Stubbs ◽

Marco Biancucci ◽

Vania Vidimar ◽

Karla J. F. Satchell

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Cell Fate ◽

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines ◽

Colorectal Cancer Cell ◽

Cancer Cell Growth ◽

Innovative Strategy ◽

Colorectal Cancer Cell Lines

AbstractRas-specific proteases to degrade RAS within cancer cells are under active development as an innovative strategy to treat tumorigenesis. The naturally occurring biological toxin effector called RAS/RAP1-specific endopeptidase (RRSP) is known to cleave all RAS within a cell, including HRAS, KRAS, NRAS and mutant KRAS G13D. Yet, our understanding of the mechanisms by which RRSP drives growth inhibition are unknown. Here, we demonstrate, using isogenic mouse fibroblasts expressing a single isoform of RAS or mutant KRAS, that RRSP equally inactivates all isoforms of RAS as well as the major oncogenic KRAS mutants. To investigate how RAS processing might lead to varying outcomes in cell fate within cancer cells, we tested RRSP against four colorectal cancer cell lines with a range of cell fates. While cell lines highly susceptible to RRSP (HCT116 and SW1463) undergo apoptosis, RRSP treatment of GP5d and SW620 cells induces G1 cell cycle arrest. In some cell lines, growth effects were dictated by rescued expression of the tumor suppressor protein p27 (Kip1). The ability of RRSP to irreversibly inhibit cancer cell growth highlights the antitumor potential of RRSP, and further warrants investigation as a potential anti-tumor therapeutic.

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Expression of P4H9-detecting molecule on spindle-shaped fibroblasts to indicate malignant phenotype of colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.539 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 539-539

Author(s):

Shozo Yokoyama ◽

Junji Ieda ◽

Naoyuki Yamamoto ◽

Yasuyuki Mitani ◽

Katsunari Takifuji ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Cancer Cell Lines ◽

Colorectal Cancer Cell ◽

Cancer Tissue ◽

Malignant Phenotype ◽

Tissue Samples ◽

Colorectal Cancer Cell Lines

539 Background: Cancer cells and fibroblasts are coordinated for cancer progression. Our previous study has shown that P4H9, produced by epitope for b2 integrin, detected a molecule on fibroblasts in mammary fat pad mouse model in response to Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expressing cancer cells. P4H9 detecting molecule (PDM) expression appeared to be associated with myofibroblast differentiation. The aim of the present study is to investigate whether PDM express on fibroblast and cancer cells in clinical tissue samples, and whether PDM expressing cells in colorectal cancer tissue are correlated with clinicopathological features of patients with colorectal cancer. Methods: Immunohistochemistry were conducted with P4H9 on clinical tissue samples from 156 patients with colorectal cancer. The risk factors for metastases and survival were calculated for clinical implication of PDM expressing spindle shaped fibroblasts. Immunofluorescence with P4H9 were performed on CCD-18Co fibroblasts and colorectal cancer cell lines, HT29 and HCT116. Results: Multivariate analysis showed that PDM expressing spindle shaped fibroblasts was an independent risk factor for lymph node metastasis, hematogenous metastasis, and short survival. Kaplan-Meier survival curve presented that PDM expressing spindle shaped fibroblasts was associated with shorter survival time (p< 0.0001). PDM expressing spindle shaped fibroblasts is associated with metastasis and shorter survival of the patients with colorectal cancer. Immunofluorescence showed that PDM expressed on CCD-18Co fibroblasts and colorectal cancer cell lines, HCT116 with fibroblast like morphology. Conclusions: PDM expressing spindle shaped fibroblasts may play a role to bring out malignant phenotype of colorectal cancer. PDM may be a new biomarker and a novel therapeutic target for patients with colorectal cancer.

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