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Journal of Experimental & Clinical... Sep 2019Colon cancer is the second leading cancer worldwide. Recurrent disease and chemotherapeutic drug resistance are very common in the advanced stage of colon cancer....
BACKGROUND
Colon cancer is the second leading cancer worldwide. Recurrent disease and chemotherapeutic drug resistance are very common in the advanced stage of colon cancer. ATP-citrate lyase (ACLY), the first-step rate-controlling enzyme in lipid synthesis, is elevated in colon cancer. However, it remains unclear about the exact role of ACLY in the development of colon cancer metastasis.
METHODS
To evaluate the role of ACLY in colon cancer metastasis, we performed cell migration and invasion assays in two ACLY-deficient colon cancer cell lines. Colon cancer mouse model is used to examine ACLY's effects on colon metastasis potentials in vivo. We analyzed the correlation between ACLY and CTNNB1 protein in 78 colon cancer patients by Pearson correlation. To finally explore the relationship of ACLY and CTNNB1, we used western blots, migration and invasion assays to confirm that ACLY may regulate metastasis by CTNNB1.
RESULTS
Our data showed that the abilities of cell migration and invasion were attenuated in ACLY-deficient HCT116 and RKO cell lines. Furthermore, we describe the mechanism of ACLY in promoting colon cancer metastasis in vitro and in vivo. ACLY could stabilize CTNNB1 (beta-catenin 1) protein by interacting, and the complex might promote CTNNB1 translocation through cytoplasm to nucleus, subsequently promote the CTNNB1 transcriptional activity and migration and invasion abilities of colon cancer cells. Immunohistochemical analysis of 78 colon cancer patients showed that the high expression levels of ACLY and CTNNB1 protein was positively correlated with metastasis of colon cancer.
CONCLUSIONS
These results shed new light on the molecular mechanism underlying colon cancer metastasis, which might help in improving therapeutic efficacy.
Topics: ATP Citrate (pro-S)-Lyase; Adult; Aged; Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colonic Neoplasms; Epithelial-Mesenchymal Transition; Female; Gene Knockdown Techniques; Humans; Male; Mice; Middle Aged; Models, Biological; Neoplasm Metastasis; Neoplasm Staging; beta Catenin
PubMed: 31511060
DOI: 10.1186/s13046-019-1391-9 -
Cellular & Molecular Biology Letters 2017MicroRNAs (miRNAs) play important roles in the growth and metastasis of colon cancer. It is known that one set of miRNAs are dysregulated in colon cancer cells, but the...
BACKGROUND
MicroRNAs (miRNAs) play important roles in the growth and metastasis of colon cancer. It is known that one set of miRNAs are dysregulated in colon cancer cells, but the mechanism of their role in cancer development is still largely unknown. Our study focuses on the role of miR-378 in colon cancer cells.
METHODS
Human colon cancer tissues and adjacent non-tumor tissues were collected from patients diagnosed in pathological examinations. In addition, human colon cancer cell lines LoVo, CaCo2, SW1116, SW480 and HCT-116, and a normal colonic mucosa cell line NCM460 were included. Quantitative RT-PCR was used to detect the miR-378 level in the clinical tissues and cell lines. In SW480 and HCT-116, miR-378 was artificially overexpressed or suppressed. Cell viability and proliferation were measured using MTT and colony formation assays, and apoptosis was detected via annexin V-PI staining and flow cytometry analysis. The transwell technique was applied to detect the migration and invasion of the colon cancer cells, and their epithelial-mesenchymal transition (EMT) was evaluated by detecting EMT-associated markers using Western blotting. Bioinformatics methods were used to predict the potential targets of miR-378, and luciferase reporter assays were performed to conform the direct binding between miR-378 and its target mRNA. The activity of the Wnt/β-catenin pathway was evaluated by detecting the key factors through Western blotting.
RESULTS
We found that miR-378 expression was low in colon cancer tissues and cell lines. Overexpression of miR-378 not only inhibits the proliferation of colon cancer cells in vitro by inducing apoptosis, but also inhibits migration and invasion by inhibiting the EMT of colon cancer cells. SDAD1 is a direct target gene of miR-378, and knockdown of SDAD1 suppresses the proliferation, migration and invasion of colon cancer cells. We also confirmed that miR-378 alleviated the malignant phenotypes of colon cancer cells by inhibiting the Wnt/β-catenin pathway.
CONCLUSION
miR-378 inhibits the proliferation, migration and invasion of colon cancer cells by targeting SDAD1, defining miR-378 as a potential target for the diagnosis and treatment of colon cancer.
Topics: Apoptosis; Cell Cycle Proteins; Cell Movement; Cell Proliferation; Colonic Neoplasms; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasm Invasiveness; Nuclear Proteins
PubMed: 28725241
DOI: 10.1186/s11658-017-0041-5 -
International Journal of Cancer Aug 2018Caspase-3 (CASP3) is a major mediator of apoptosis activated during cellular exposure to cytotoxic drugs, radiotherapy or immunotherapy. It is often used as a marker for...
Caspase-3 (CASP3) is a major mediator of apoptosis activated during cellular exposure to cytotoxic drugs, radiotherapy or immunotherapy. It is often used as a marker for efficacy of cancer therapy. However, recent reports indicate that caspase-3 has also non-apoptotic roles such as promotion of tumor relapse and tumor angiogenesis. Therefore, the roles of caspase-3 in tumor progression remain to be defined clearly. In our study, we established caspase-3 knockout (KO) colon cancer cell lines by use of the CRISPR technology. In vitro, caspase-3 knockout HCT116 cells were significantly less clonogenic in soft agar assays. They were also significantly less invasive and more sensitive to radiation and mitomycin C than control cells. In vivo, CASP3KO cells formed tumors at rates similar to control cells but were significantly more sensitive to radiotherapy. They were also less prone to pulmonary metastasis when inoculated either subcutaneously or intravenously. At the mechanistic level, caspase-3 gene knockout appeared to cause reduced EMT phenotypes when compared to parental HCT116 cells. Indeed, they showed significantly increased E-cadherin expression, reduced N-cadherin, Snail, Slug and ZEB1 expression than control cells. Therefore, therapeutic targeting of caspase-3 may not only increase the sensitivity of cancer cell to chemotherapy and radiotherapy, but also inhibit cancer cell invasion and metastasis.
Topics: Blotting, Western; Caspase 3; Cell Line, Tumor; Cell Movement; Clustered Regularly Interspaced Short Palindromic Repeats; Colonic Neoplasms; Drug Resistance, Neoplasm; Enzyme-Linked Immunosorbent Assay; Epithelial-Mesenchymal Transition; Gene Knockout Techniques; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Radiation Tolerance
PubMed: 29524226
DOI: 10.1002/ijc.31374 -
Molecular Cancer Apr 2021
Topics: Biomarkers, Tumor; Cancer-Associated Fibroblasts; Colonic Neoplasms; Exosomes; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Staging; Prognosis; Tumor Microenvironment
PubMed: 33926453
DOI: 10.1186/s12943-021-01367-x -
Journal of Clinical Oncology : Official... Jul 2010Prior reports have indicated that patients with colon cancer who demonstrate high-level microsatellite instability (MSI-H) or defective DNA mismatch repair (dMMR) have...
PURPOSE
Prior reports have indicated that patients with colon cancer who demonstrate high-level microsatellite instability (MSI-H) or defective DNA mismatch repair (dMMR) have improved survival and receive no benefit from fluorouracil (FU) -based adjuvant therapy compared with patients who have microsatellite-stable or proficient mismatch repair (pMMR) tumors. We examined MMR status as a predictor of adjuvant therapy benefit in patients with stages II and III colon cancer.
METHODS
MSI assay or immunohistochemistry for MMR proteins were performed on 457 patients who were previously randomly assigned to FU-based therapy (either FU + levamisole or FU + leucovorin; n = 229) versus no postsurgical treatment (n = 228). Data were subsequently pooled with data from a previous analysis. The primary end point was disease-free survival (DFS).
RESULTS
Overall, 70 (15%) of 457 patients exhibited dMMR. Adjuvant therapy significantly improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.93; P = .02) in patients with pMMR tumors. Patients with dMMR tumors receiving FU had no improvement in DFS (HR, 1.10; 95% CI, 0.42 to 2.91; P = .85) compared with those randomly assigned to surgery alone. In the pooled data set of 1,027 patients (n = 165 with dMMR), these findings were maintained; in patients with stage II disease and with dMMR tumors, treatment was associated with reduced overall survival (HR, 2.95; 95% CI, 1.02 to 8.54; P = .04).
CONCLUSION
Patient stratification by MMR status may provide a more tailored approach to colon cancer adjuvant therapy. These data support MMR status assessment for patients being considered for FU therapy alone and consideration of MMR status in treatment decision making.
Topics: Aged; Antimetabolites, Antineoplastic; Biomarkers; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; DNA Mismatch Repair; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Male; Middle Aged; Prognosis; Randomized Controlled Trials as Topic
PubMed: 20498393
DOI: 10.1200/JCO.2009.27.1825 -
EMBO Reports Apr 2023Colon tumors of the mesenchymal subtype have the lowest overall survival. Snail1 is essential for the acquisition of this phenotype, characterized by increased tumor...
Colon tumors of the mesenchymal subtype have the lowest overall survival. Snail1 is essential for the acquisition of this phenotype, characterized by increased tumor stemness and invasion, and high resistance to chemotherapy. Here, we find that Snail1 expression in colon tumor cells is dependent on an autocrine noncanonical Wnt pathway. Accordingly, depletion of Ror2, the co-receptor for noncanonical Wnts such as Wnt5a, potently decreases Snail1 expression. Wnt5a, Ror2, and Snail1 participate in a self-stimulatory feedback loop since Wnt5a increases its own synthesis in a Ror2- and Snail1-dependent fashion. This Wnt5a/Ror2/Snail1 axis controls tumor invasion, chemoresistance, and formation of tumor spheres. It also stimulates TGFβ synthesis; consequently, tumor cells expressing Snail1 are more efficient in activating cancer-associated fibroblasts than the corresponding controls. Ror2 downmodulation or inhibition of the Wnt5a pathway decreases Snail1 expression in primary colon tumor cells and their ability to form tumors and liver metastases. Finally, the expression of SNAI1, ROR2, and WNT5A correlates in human colon and other tumors. These results identify inhibition of the noncanonical Wnt pathway as a putative colon tumor therapy.
Topics: Humans; Wnt Signaling Pathway; Drug Resistance, Neoplasm; Colonic Neoplasms; Fibroblasts
PubMed: 36704936
DOI: 10.15252/embr.202254895 -
Molecules (Basel, Switzerland) May 2020Colorectal carcinoma (CRC) is the leading cause of cancer-related deaths worldwide. Despite advances in prevention and treatment modalities for CRC, rapidly developing... (Review)
Review
Colorectal carcinoma (CRC) is the leading cause of cancer-related deaths worldwide. Despite advances in prevention and treatment modalities for CRC, rapidly developing resistance to chemotherapy limits its effectiveness. For that reason, it is important to better understand the mechanisms that undergird the process of chemoresistance to enable design of novel anticancer agents specifically targeting malignant properties of cancer cells. Over recent decades, bioactive sphingolipid species have come under the spotlight for their recognized role in cancer development and progression, and the evidence has surfaced to support their role as regulators of anti-cancer drug resistance. Colon cancer is characterized by a shift in sphingolipid balance that favors the production and accumulation of oncogenic species such as sphingosine 1-phosphate (S1P). S1P is known to govern the processes that facilitate cancer cell growth and progression including proliferation, survival, migration, invasion and inflammation. In this review paper, we will give a comprehensive overview of current literature findings on the molecular mechanisms by which S1P turnover, transport and signaling via receptor-dependent and independent pathways shape colon cancer cell behavior and influence treatment outcome in colon cancer. Combining available modulators of S1P metabolism and signaling with standard chemotherapy drugs could provide a rational approach to achieve enhanced therapeutic response, diminish chemoresistance development and improve the survival outcome in CRC patients.
Topics: Antineoplastic Agents; Cell Proliferation; Chemoprevention; Colonic Neoplasms; Drug Resistance, Neoplasm; Humans; Lysophospholipids; Signal Transduction; Sphingolipids; Sphingosine
PubMed: 32456134
DOI: 10.3390/molecules25102436 -
World Journal of Gastroenterology Jun 2015The colon is derived from the embryological midgut and hindgut separately, with the right colon and left colon having different features with regards to both anatomical... (Review)
Review
The colon is derived from the embryological midgut and hindgut separately, with the right colon and left colon having different features with regards to both anatomical and physiological characteristics. Cancers located in the right and left colon are referred to as right colon cancer (RCC) and left colon cancer (LCC), respectively, based on their apparent anatomical positions. Increasing evidence supports the notion that not only are there differences in treatment strategies when dealing with RCC and LCC, but molecular features also vary between them, not to mention the distinguishing clinical manifestations. Disease-free survival after radical surgery of both RCC and LCC are similar. In the treatment of RCC, the benefit gained from adjuvant FOLFIRI chemotherapy is superior, or at least similar, to LCC, but inferior to LCC if FOLFOX regimen is applied. On the other hand, metastatic LCC exhibits longer survival than that of RCC in a palliative chemotherapy setting. For KRAS wild-type cancers, LCC benefits more from cetuximab treatment than RCC. Moreover, advanced LCC shows a higher sensitivity to bevacizumab treatment in comparison with advanced RCC. Significant varieties exist at the molecular level between RCC and LCC, which may serve as the cause of all apparent differences. With respect to carcinogenesis mechanisms, RCC is associated with known gene types, such as MMR, KRAS, BRAF, and miRNA-31, while LCC is associated with CIN, p53, NRAS, miRNA-146a, miRNA-147b, and miRNA-1288. Regarding protein expression, RCC is related to GNAS, NQO1, telomerase activity, P-PDH, and annexin A10, while LCC is related to Topo I, TS, and EGFR. In addition, separated pathways dominate progression to relapse in RCC and LCC. Therefore, RCC and LCC should be regarded as two heterogeneous entities, with this heterogeneity being used to stratify patients in order for them to have the optimal, current, and novel therapeutic strategies in clinical practice. Additional research is needed to uncover further differences between RCC and LCC.
Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Disease Progression; Disease-Free Survival; Genetic Predisposition to Disease; Humans; Molecular Targeted Therapy; Mutation; Neoplasm Recurrence, Local; Phenotype; Risk Factors; Time Factors; Treatment Outcome
PubMed: 26074686
DOI: 10.3748/wjg.v21.i21.6470 -
Journal of the American College of... Feb 2021The Affordable Care Act facilitated improved insurance coverage for states that expanded Medicaid coverage, but the impact on cancer outcomes is unclear. This study...
BACKGROUND
The Affordable Care Act facilitated improved insurance coverage for states that expanded Medicaid coverage, but the impact on cancer outcomes is unclear. This study compared changes in the diagnosis and management of colon cancer in states that did and did not participate in Medicaid expansion.
STUDY DESIGN
Using a quasi-experimental difference-in-differences (DID) approach, we analyzed Medicaid and uninsured patients in the National Cancer Data Base during 2 time periods: pre (2011-2012) and post expansion (2015-2016). Patients in non-expansion states were compared with those in January 2014 expansion states with regard to changes in patient and facility characteristics, cancer staging, treatment decisions, and surgical outcomes.
RESULTS
Along with increased Medicaid coverage (DID = 20.27; p < 0.001), patients in expansion states had an increase in stage I diagnoses (DID = 2.97; p = 0.035), distance traveled (miles, DID = 6.67; p = 0.005), and treatment at integrated network programs (DID = 2.67; p = 0.045). More early-stage patients were treated within 30 days (DID = 7.24; p = 0.035) and more stage IV patients received palliative care (DID = 5.01; p = 0.048). Among surgical patients, Medicaid expansion correlated with fewer urgent cases (< 7 days, DID = -5.88; p = 0.008) and more minimally invasive surgery (DID = 5.00; p = 0.022). There were no observed differences in postoperative outcomes or adjuvant chemotherapy.
CONCLUSIONS
Medicaid expansion correlated with earlier diagnosis, enhanced access, and improved surgical care for colon cancer patients. These findings highlight the importance of improving health insurance coverage and can help guide future policy efforts.
Topics: Accountable Care Organizations; Adult; Chemotherapy, Adjuvant; Colonic Neoplasms; Early Detection of Cancer; Female; Health Policy; Health Services Accessibility; Humans; Male; Medicaid; Medically Uninsured; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Palliative Care; Retrospective Studies; Treatment Outcome; United States
PubMed: 33242599
DOI: 10.1016/j.jamcollsurg.2020.10.021 -
Surgical Endoscopy Dec 2017In colon cancer, T4 stage is still assumed to be a relative contraindication for laparoscopic surgery considering the oncological safety. The aim of this systematic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
In colon cancer, T4 stage is still assumed to be a relative contraindication for laparoscopic surgery considering the oncological safety. The aim of this systematic review with meta-analysis was to evaluate short- and long-term oncological outcomes after laparoscopic surgery for T4 colon cancer, and to compare these with open surgery.
METHODS
Using systematic review of literature, studies reporting on radicality of resection, disease-free survival (DFS), and/or overall survival (OS) after laparoscopic surgery for T4 colon cancer were identified, with or without a control group of open surgery. Pooled proportions and risk ratios were calculated using an inverse variance method.
RESULTS
Thirteen observational cohort studies published between 2012 and 2017 were included, together consisting of 1217 patients that received laparoscopic surgery and 1357 with an open procedure. The proportion of multivisceral resections was larger in the open group in five studies. Based on 11 studies, the pooled proportion of R0 resection was 0.96 (95% CI: 0.91-0.99) and 0.96 (95% CI: 0.90-0.98) after laparoscopic and open surgery, respectively. Analysing (mainly) T4a subgroups in 6 evaluable studies revealed pooled R0 resection rates of 0.94 in both groups. No significant differences were found between laparoscopic and open surgery for any survival measure: RR 1.07 (95% CI: 0.96-1.20) for 3-year DFS, RR 1.04 (95% CI: 0.95-1.15) for 5-year DFS, RR 1.07 (95% CI: 0.99-1.14) for 3-year OS, and RR 1.05 (95% CI: 0.98-1.12) for 5-year OS.
CONCLUSION
Literature on laparoscopic surgery for T4 colon cancer is restricted to non-randomized comparisons with substantial allocation bias. Laparoscopic surgery for T4a tumours might be safe, whereas for T4b colon cancer requiring multivisceral resection it should be applied with caution.
Topics: Colectomy; Colonic Neoplasms; Humans; Laparoscopy; Neoplasm Staging; Treatment Outcome
PubMed: 28432461
DOI: 10.1007/s00464-017-5544-7