MACC1 expression as a candidate prognostic biomarker in colorectal cancer patients receiving adjuvant oxaliplatin-based therapy.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 567-567 ◽  
Author(s):  
Lynn Katherine Symonds ◽  
Kelsey K. Baker ◽  
Mary Weber Redman ◽  
Lisa Koch ◽  
Kelly Carter ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cox Regression ◽  
Prognostic Biomarker ◽  
Patient Characteristics ◽  
Hazard Ratios ◽  
Platinum Based Chemotherapy ◽  
Tumor Mutational Burden ◽  
Colorectal Cancer Patients

567 Background: MACC1, part of the HGF-MET pathway, drives proliferation and regulation of MET expression in vitro. In vivo, MACC1 is associated with tumor progression and studies suggest greater MACC1 expression is associated with resistance to platinum-based chemotherapy. We hypothesized that MACC1 may be a prognostic biomarker in colorectal cancer (CRC). Methods: MACC1 expression was evaluated by immunohistochemistry on tumor microarrays (N = 428). Patients were stage I-III CRC who received an oxaliplatin-based regimen (either with 5-FU (FOLFOX) or capecitabine (XELOX)) within the HeCOG 6C/08 observational study. MACC1 expression was assessed by a blinded GI pathologist using a scale ranging from 0 (no staining) to 3+ (strong expression). Each patient had at least 3 samples and the strongest result was used for the final score. MACC1 positivity was defined as ≥2+ expression and 0-1+ as MACC1-. Cox regression models were used to estimate hazard ratios (HR) for the association of MACC1 expression with patient characteristics, disease-free (DFS), and overall survival (OS). Results: 400/428 CRC tumors were evaluable: 322 (80.5%) were MACC1+ and 78 (19.5%) MACC1-. Mucinous features were less likely in MACC1+ patients (24% vs. 38%, p = 0.02). Other unfavorable features including grade, lymphovascular invasion, perineural invasion, and tumor mutational burden were not significantly different. There was no difference for stage, microsatellite instability, BRAF, KRAS, or NRASstatus between MACC1+/- cancers. There was a trend towards worse survival in MACC1+ patients regardless of treatment (DFS HR 1.55 [95% CI: 0.87, 2.76], OS HR 1.59 [95% CI 0.74, 3.4]). This difference was not statistically significant for OS (p = 0.26) or DFS (p = 0.08) even when stratified by clinicopathologic variables. Conclusions: Patients with MACC1+ CRC tumors who received adjuvant oxaliplatin-based therapy were less likely to have mucinous histology. They had a trend toward independently worse survival that was not significant when accounting for stage and clinicopathologic variables. Studies focused on the predictive role of MACC1 and oxaliplatin in stage III CRC are in progress.

scholarly journals Necroptosis regulates tumor repopulation after radiotherapy via RIP1/RIP3/MLKL/JNK/IL8 pathway

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Yiwei Wang ◽  
Minghui Zhao ◽  
Sijia He ◽  
Yuntao Luo ◽  
Yucui Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Stimulation ◽  
Underlying Mechanism ◽  
Promoting Effect ◽  
Clinical Prognosis ◽  
Associated Proteins ◽  
Radiation Induced ◽  
Colorectal Cancer Patients

Abstract Background Tumor cell repopulation after radiotherapy is a major cause for the tumor radioresistance and recurrence. This study aims to investigate the underlying mechanism of tumor repopulation after radiotherapy, with focus on whether and how necroptosis takes part in this process. Methods Necroptosis after irradiation were examined in vitro and in vivo. And the growth-promoting effect of necroptotic cells was investigated by chemical inhibitors or shRNA against necroptosis associated proteins and genes in in vitro and in vivo tumor repopulation models. Downstream relevance factors of necroptosis were identified by western blot and chemiluminescent immunoassays. Finally, the immunohistochemistry staining of identified necroptosis association growth stimulation factor was conducted in human colorectal tumor specimens to verify the relationship with clinical outcome. Results Radiation-induced necroptosis depended on activation of RIP1/RIP3/MLKL pathway, and the evidence in vitro and in vivo demonstrated that the inhibition of necroptosis attenuated growth-stimulating effects of irradiated tumor cells on living tumor reporter cells. The JNK/IL-8 were identified as downstream molecules of pMLKL during necroptosis, and inhibition of JNK, IL-8 or IL-8 receptor significantly reduced tumor repopulation after radiotherapy. Moreover, the high expression of IL-8 was associated with poor clinical prognosis in colorectal cancer patients. Conclusions Necroptosis associated tumor repopulation after radiotherapy depended on activation of RIP1/RIP3/MLKL/JNK/IL-8 pathway. This novel pathway provided new insight into understanding the mechanism of tumor radioresistance and repopulation, and MLKL/JNK/IL-8 could be developed as promising targets for blocking tumor repopulation to enhance the efficacy of colorectal cancer radiotherapy.

scholarly journals A specific Upregulated lncRNA in Colorectal Cancer Promotes Cancer Progression by Modulating miR-185-5p/CCND2 Axis

2021 ◽  
Author(s):  
Junshu Li ◽  
Yanhong Ji ◽  
Na Chen ◽  
Huiling Wang ◽  
Chao Fang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Network Analysis ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Gene Mutations ◽  
Disease Free Survival ◽  
Luciferase Reporter ◽  
Colorectal Cancer Patients

Abstract BackgroundAdenomatous polyposis coli (APC) gene mutations were found in most colorectal cancer patients and functioned as an important inducer of tumorigenesis. Long non-coding RNA (lncRNA) plays a crucial role in the pathogenesis of various diseases, including colorectal cancer (CRC). Here we investigated the role of SURC which is specific upregulated in CRC progression. MethodsBased on the previous microarray results, weighted correlation network analysis (WGCNA) and lncRNA-mRNA co-expression network analysis were used to identify a lncRNA (SURC) and found it was specific up-regulated in CRC patients by qPCR and FISH staining. Chromatin immunoprecipitation (ChIP) assay was used to demonstrate the regulatory effect and mechanism of APC mutation on SURC expression. The effects of SURC on proliferation and cell cycle were determined by in vitro and in vivo experiments. Chromatin Isolation by RNA Purification (CHIRP) and luciferase reporter assay were carried out to illustrate the interaction between SURC, miR-185-5p and CCND2.ResultsWe found that SURC was specific up-regulated in CRC, but not in other solid tumor, when compared with normal adjacent tissues. High expression of SURC correlates with poorer disease-free survival and overall survival of CRC patients. Mutated APC protein resulted in stabilization of β-catenin in CRC, which promotes the transcription of SURC via binding to its promoter. Knockdown of SURC impaired CRC cell proliferation, colony formation and CRC tumor growth. Mechanistically, after transcription, SURC was transferred to cytoplasm and inhibits miR-185-5p expression via binding to miR-185-5p and inhibiting the synthesis of miR-185-5p from pri-miR-185-5p, which results in CCND2 expression.ConclusionCollectively, these results indicated that SURC promoted CRC tumor growth via interacting with miR-185-5p and regulating the activity of miR-185-5p/CCND2 axis which would be a novel diagnosis and prognosis prediction target for CRC.

scholarly journals Long noncoding RNA RP11-757G1.5 sponges miR-139-5p and upregulates YAP1 thereby promoting the proliferation and liver, spleen metastasis of colorectal cancer

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Xiaojian Zhu ◽  
Fanqin Bu ◽  
Ting Tan ◽  
Qilin Luo ◽  
Jinfeng Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
In Situ Hybridization ◽  
Cox Regression ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Cox Regression Analysis

Abstract Background Accumulating evidence indicates that long non-coding RNAs (lncRNAs) acting as crucial regulators in tumorigenesis. However, its biological functions of lncRNAs in colorectal cancer (CRC) have not been systematically clarified. Methods An unbiased screening was performed to identify disregulated lncRNAs revealed to be implicated in CRC carcinogenesis according to an online-available data dataset. In situ hybridization (ISH), RT-qPCR and RNA fluorescence in situ hybridization (RNA-FISH) were applied to detect RP11-757G1.5 expression in CRC tissues and cell lines. The associations of RP11-757G1.5 with clinicopathological characteristics were analyzed. Their effects on prognosis were analyzed by the Kaplan-Meier analysis, Log-rank test, Univariate and Multivariate Cox regression analysis. The potential biological function of RP11-757G1.5 in CRC was investigated by Colony formation, Edu cell proliferation, Flow cytometry, Wound healing and Transwell assays. Bioinformatics binding site analysis, Luciferase reporter assay, Ago2 immunoprecipitation assays, RNA pull-down assay, RT-qPCR and Western blotting were utilized to demonstrate the mechanism of RP11-757G1.5 acts as a molecular sponge of miR-139-5p to regulate the expression of YAP1. Finally, we further explore the potential role of RP11-757G1.5 in CRC orthotopic xenografts in vivo. Results We discovered a novel oncogenic lncRNA RP11-757G1.5, that was overexpressed in CRC tissues, especially in aggressive cases. Moreover, up-regulation of RP11-757G1.5 strongly correlated with poor clinical outcomes of patients with CRC. Functional analyses revealed that RP11-757G1.5 promoted cell proliferation in vitro and in vivo. Furthermore, RP11-757G1.5 stimulated cell migration and invasion in vitro and in vivo. Mechanistic studies illustrated that RP11-757G1.5 regulated the expression of YAP1 through sponging miR-139-5p and inhibiting its activity thereby promoting CRC progression and development. Conclusions Altogether, these results reveal a novel RP11-757G1.5/miR-139-5p/YAP1 regulatory axis that participates in CRC carcinogenesis and progression.

scholarly journals Expression of Long Non-Coding RNA PANDAR and its Prognostic Value in Colorectal Cancer Patients

2017 ◽  
Vol 32 (2) ◽  
pp. 218-223 ◽  
Author(s):  
Xiangke Li ◽  
Feng Wang ◽  
Yan Sun ◽  
Qingxia Fan ◽  
Guangfei Cui
Keyword(s):  
Colorectal Cancer ◽  
Cox Regression ◽  
Human Cancer ◽  
Expression Level ◽  
Migration And Invasion ◽  
Cox Regression Analysis ◽  
Relative Expression Level ◽  
Kaplan Meier ◽  
Colorectal Cancer Patients

Background Long noncoding RNAs (lncRNAs) are emerging as key molecules in human cancer. In the present study, we explored the role of the lncRNA PANDAR in colorectal cancer (CRC). Methods The relative expression level of lncRNA PANDAR in CRC tissues and cell lines was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The associations between PANDAR expression and clinicopathological features of CRC patients were further analyzed. Kaplan-Meier survival analysis was performed to evaluate the value of PANDAR in the prognosis of CRC patients. Furthermore, the biological function of PANDAR on CRC cell growth, apoptosis and mobility was investigated through MTT, flow cytometry, transwell migration and invasion assays in vitro. Results The expression level of PANDAR was higher in CRC tissues and cells compared with adjacent nontumor tissues and normal colonic cell line NCM460. PANDAR expression was significantly correlated with local invasion, lymph node metastasis and TNM stage. Kaplan-Meier analysis showed that patients with high PANDAR expression had poorer overall survival than patients with low PANDAR expression. Multivariate Cox regression analysis indicated that PANDAR might be an independent prognostic factor for CRC patients. Furthermore, PANDAR knockdown significantly inhibited cell proliferation, cycle progression, migration and invasion of CRC in vitro. Conclusions Our results suggest that high expression of PANDAR was involved in CRC progression and could act as an independent biomarker for prognosis of CRC patients.

scholarly journals Long noncoding RNA RP11-757G1.5 sponges miR-139-5p and upregulates YAP1 thereby promoting the proliferation and liver, spleen metastasis of colorectal cancer

2020 ◽  
Author(s):  
xiaojian zhu ◽  
Fanqin Bu ◽  
Ting Tan ◽  
Qilin Luo ◽  
Jingfeng Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
In Situ Hybridization ◽  
Cox Regression ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Cox Regression Analysis

Abstract Background: Accumulating evidence indicates that long non-coding RNAs (lncRNAs) acting as crucial regulators in tumorigenesis. However, its biological functions of lncRNAs in colorectal cancer (CRC) have not been systematically clarified. Methods: An unbiased screening was performed to identify disregulated lncRNAs revealed to be implicated in CRC carcinogenesis according to an online-available data dataset. In situ hybridization (ISH), RT-qPCR and RNA fluorescence in situ hybridization (RNA-FISH) were applied to detect RP11-757G1.5 expression in CRC tissues and cell lines. The associations of RP11-757G1.5 with clinicopathological characteristics were analyzed. Their effects on prognosis were analyzed by the Kaplan-Meier analysis, Log-rank test, Univariate and Multivariate Cox regression analysis. The potential biological function of RP11-757G1.5 in CRC was investigated by Colony formation, Edu cell proliferation, Flow cytometry, Wound healing and Transwell assays. Bioinformatics binding site analysis, Luciferase reporter assay, Ago2 immunoprecipitation assays, RNA pull-down assay, RT-qPCR and Western blotting were utilized to demonstrate the mechanism of RP11-757G1.5 acts as a molecular sponge of miR-139-5p to regulate the expression of YAP1. Finally, we further explore the potential role of RP11-757G1.5 in CRC orthotopic xenografts in vivio . Results: We discovered a novel oncogenic lncRNA RP11-757G1.5, that was overexpressed in CRC tissues, especially in aggressive cases. Moreover, up-regulation of RP11-757G1.5 strongly correlated with poor clinical outcomes of patients with CRC. Functional analyses revealed that RP11-757G1.5 promoted cell proliferation in vitro and in vivo . Furthermore, RP11-757G1.5 stimulated cell migration and invasion in vitro and in vivo . Mechanistic studies illustrated that RP11-757G1.5 regulated the expression of YAP1 through sponging miR-139-5p and inhibiting its activity thereby promoting CRC progression and development. Conclusions: Altogether, these results reveal a novel RP11-757G1.5/miR-139-5p/YAP1 regulatory axis that participates in CRC carcinogenesis and progression.

scholarly journals STK33/ERK2 signal pathway contribute the tumorigenesis of colorectal cancer HCT15 cells

2019 ◽  
Vol 19 ◽  
Author(s):  
Shengjun Zhang ◽  
Minli Liu ◽  
Haoyu Wu ◽  
Kaiyu Wang
Keyword(s):  
Colorectal Cancer ◽  
Ex Vivo ◽  
Kinase Assay ◽  
In Vivo Studies ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Upstream Kinase ◽  
Colorectal Cancer Patients

: Serine/threonine kinase 33 (STK33) is a serine/threonine kinase, and participates in many apoptotic process. Herein, we found that the extracellular signal-regulated kinase 2 (ERK2) was a substrate of STK33. STK33 phosphorylated ERK2and increased the activity of ERK2 and promote the tumorigenesis of colorectal cancer HCT15 cells. Clinical simple showed that STK33 was highly expression in colorectal cells and tissues. Ex vivo and in vivo studies demonstrated that STK33 accelerate tumorigenic properties in JB6C141 cells and athymic nude rats. In vitro kinase assay results indicated that STK33 can phosphorylate ERK2. Ex vivo studies further showed that STK33 can bind with ERK2 and take part in the regulation of ERKs signaling pathway. In short, our results showed that STK33 is a novel upstream kinase of ERK2. It may provide a better prospect for STK33 based prevention and treatment for colorectal cancer patients.

scholarly journals ZBTB7A functioned as an oncogene in colorectal cancer

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Li Wang ◽  
Meng-Xia Zhang ◽  
Mei-Fang Zhang ◽  
Zi-Wei Tu
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Biomarker ◽  
Poor Survival ◽  
Clinical Value ◽  
Functional Roles ◽  
Btb Domain ◽  
Proliferation In Vitro ◽  
Diagnostic And Prognostic Value

Abstract Background Despite zinc finger and BTB domain-containing 7A (ZBTB7A) documented importance in multiple tumors, the function and clinical value in Colorectal cancer (CRC) remain elusive. The aim of this study was to evaluate the functional roles and the clinical value of ZBTB7A in CRC progression. Methods The level of ZBTB7A was detected in a large cohort of CRC patients (n = 189) by immunohistochemistry (IHC), and we analyzed the diagnostic and prognostic value of the protein. In addition, the functional roles of ZBTB7A on CRC were explored in vitro and in vivo. Results Survival analyses indicated that patients with high ZBTB7A expression made the prognosis worse (P = 0.024). Functionally, knockdown of ZBTB7A could markedly inhibit tumor proliferation in vitro and in vivo, whereas ZBTB7A overexpression displayed the opposite results. Conclusions ZBTB7A was associated with poor survival outcomes and functioned as an oncogene in CRC patients, indicating that it is a potential prognostic biomarker and therapeutic target for CRC patients.

scholarly journals Chemosensitivity of Patient-Derived Cancer Stem Cells Identifies Colorectal Cancer Patients with Potential Benefit from FGFR Inhibitor Therapy

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2010
Author(s):  
Takehito Yamamoto ◽  
Hiroyuki Miyoshi ◽  
Fumihiko Kakizaki ◽  
Hisatsugu Maekawa ◽  
Tadayoshi Yamaura ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Patients ◽  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
Inhibitor Therapy ◽  
Epithelial Stem Cells ◽  
Colorectal Cancer Patients

Some colorectal cancer patients harboring FGFR (fibroblast growth factor receptor) genetic alterations, such as copy number gain, mutation, and/or mRNA overexpression, were selected for enrollment in several recent clinical trials of FGFR inhibitor, because these genetic alterations were preclinically reported to be associated with FGFR inhibitor sensitivity as well as poor prognosis, invasiveness, and/or metastatic potential. However, few enrolled patients were responsive to FGFR inhibitors. Thus, practical strategies are eagerly awaited that can stratify patients for the subset that potentially responds to FGFR inhibitor chemotherapy. In the present study, we evaluated the sensitivity to FGFR inhibitor erdafitinib on 25 patient-derived tumor-initiating cell (TIC) spheroid lines carrying wild-type RAS and RAF genes, both in vitro and in vivo. Then, we assessed possible correlations between the sensitivity and the genetic/genomic data of the spheroid lines tested. Upon their exposure to erdafitinib, seven lines (7/25, 28%) responded significantly. Normal colonic epithelial stem cells were unaffected by the inhibitors. Moreover, the combination of erdafitinib with EGFR inhibitor erlotinib showed stronger growth inhibition than either drug alone, as efficacy was observed in 21 lines (84%) including 14 (56%) that were insensitive to erdafitinib alone. The in vitro erdafitinib response was accurately reflected on mouse xenografts of TIC spheroid lines. However, we found little correlation between their genetic/genomic alterations of TIC spheroids and the sensitivity to the FGFR inhibitor. Accordingly, we propose that direct testing of the patient-derived spheroids in vitro is one of the most reliable personalized methods in FGFR-inhibitor therapy of colorectal cancer patients.

scholarly journals Cytoplasmic p21 Mediates 5-Fluorouracil Resistance by Inhibiting Pro-Apoptotic Chk2

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 373 ◽  
Author(s):  
Arnatchai Maiuthed ◽  
Chuanpit Ninsontia ◽  
Katharina Erlenbach-Wuensch ◽  
Benardina Ndreshkjana ◽  
Julienne Muenzner ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Chorioallantoic Membrane ◽  
Proximity Ligation Assay ◽  
Proximity Ligation ◽  
Cancer Aggressiveness ◽  
Localization Signal ◽  
Colorectal Cancer Patients

The oncogenic cytoplasmic p21 contributes to cancer aggressiveness and chemotherapeutic failure. However, the molecular mechanisms remain obscure. Here, we show for the first time that cytoplasmic p21 mediates 5-Fluorouracil (5FU) resistance by shuttling p-Chk2 out of the nucleus to protect the tumor cells from its pro-apoptotic functions. We observed that cytoplasmic p21 levels were up-regulated in 5FU-resistant colorectal cancer cells in vitro and the in vivo Chorioallantoic membrane (CAM) model. Kinase array analysis revealed that p-Chk2 is a key target of cytoplasmic p21. Importantly, cytoplasmic form of p21 mediated by p21T145D transfection diminished p-Chk2-mediated activation of E2F1 and apoptosis induction. Co-immunoprecipitation, immunofluorescence, and proximity ligation assay showed that p21 forms a complex with p-Chk2 under 5FU exposure. Using in silico computer modeling, we suggest that the p21/p-Chk2 interaction hindered the nuclear localization signal of p-Chk2, and therefore, the complex is exported out of the nucleus. These findings unravel a novel mechanism regarding an oncogenic role of p21 in regulation of resistance to 5FU-based chemotherapy. We suggest a possible value of cytoplasmic p21 as a prognosis marker and a therapeutic target in colorectal cancer patients.

scholarly journals PGE2-JNK signaling axis non-canonically promotes Gli activation by protecting Gli2 from ubiquitin-proteasomal degradation

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Jun Yang ◽  
Juan Wang ◽  
Yuan Liu ◽  
Yu Zhang ◽  
Wenjing Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Proteasomal Degradation ◽  
Colorectal Cancers ◽  
Independent Manner ◽  
Colorectal Cancer Cells ◽  
Signaling Axis ◽  
Colorectal Cancer Patients

AbstractBoth bench and bedside investigations have challenged the supportive role of Hedgehog (Hh) activity in the progression of colorectal cancers, thus raising a critical need to further deeply determine the contribution of Hh to the growth of colorectal cancer. Combining multiple complementary means, including in vitro and in vivo inflammatory colorectal cancer models, and pathological analysis of clinical colorectal cancer patients samples. We report that colorectal cancer cells hijack prostaglandin E2 (PGE2) to non-canonically promote Hh transcriptional factor Gli activity and Gli-dependent proliferation of colorectal cancer cells in a Smo-independent manner. Mechanistically, PGE2 activates c-Jun N-terminal kinase (JNK), which in turn enables Gli2 to evade ubiquitin-proteasomal degradation by phosphorylating Gli2 at Thr1546. This study not only presents evidence for understanding the contribution of Hh to colorectal cancers, but also provides a novel molecular portrait underlying how PGE2-activated JNK fine-tunes the evasion of Gli2 from ubiquitin-proteasomal degradation. Therefore, it proposes a rationale for the future evaluation of chemopreventive and selective therapeutic strategies for colorectal cancers by targeting PGE2-JNK-Gli signaling route.

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