scholarly journals MYH9-dependent polarization of ATG9B promotes colorectal cancer metastasis by accelerating focal adhesion assembly

2021 ◽  
Author(s):  
Yan Zhong ◽  
Ting Long ◽  
Chuan-Sha Gu ◽  
Jing-Yi Tang ◽  
Ling-Fang Gao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Focal Adhesion ◽  
Poor Prognosis ◽  
Cancer Metastasis ◽  
Integrin Β1 ◽  
Independent Manner ◽  
Interacting Protein ◽  
Tumour Metastasis ◽  
Elevated Expression ◽  
Dependent Polarization

AbstractTumour metastasis is a major reason accounting for the poor prognosis of colorectal cancer (CRC), and the discovery of targets in the primary tumours that can predict the risk of CRC metastasis is now urgently needed. In this study, we identified autophagy-related protein 9B (ATG9B) as a key potential target gene for CRC metastasis. High expression of ATG9B in tumour significantly increased the risk of metastasis and poor prognosis of CRC. Mechanistically, we further find that ATG9B promoted CRC invasion mainly through autophagy-independent manner. MYH9 is the pivotal interacting protein for ATG9B functioning, which directly binds to cytoplasmic peptide segments aa368–411 of ATG9B by its head domain. Furthermore, the combination of ATG9B and MYH9 enhance the stability of each other by decreasing their binding to E3 ubiquitin ligase STUB1, therefore preventing them from ubiquitin-mediated degradation, which further amplified the effect of ATG9B and MYH9 in CRC cells. During CRC cell invasion, ATG9B is transported to the cell edge with the assistance of MYH9 and accelerates focal adhesion (FA) assembly through mediating the interaction of endocytosed integrin β1 and Talin-1, which facilitated to integrin β1 activation. Clinically, upregulated expression of ATG9B in human CRC tissue is always accompanied with highly elevated expression of MYH9 and associated with advanced CRC stage and poor prognosis. Taken together, this study highlighted the important role of ATG9B in CRC metastasis by promoting focal adhesion assembly, and ATG9B together with MYH9 can provide a pair of potential therapeutic targets for preventing CRC progression.

scholarly journals IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Chenyang Qiao ◽  
Wenjie Huang ◽  
Jie Chen ◽  
Weibo Feng ◽  
Tongyue Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Cancer Metastasis ◽  
Combined Treatment ◽  
Insulin Like Growth Factor ◽  
Atp Citrate Lyase ◽  
Citrate Lyase ◽  
Elevated Expression ◽  
Igf1r Inhibitor ◽  
Colorectal Cancer Metastasis

AbstractMetastasis is the major reason for the high mortality of colorectal cancer (CRC) patients and its molecular mechanism remains unclear. Here, we report a novel role of Homeobox A13 (HOXA13), a member of the Homeobox (HOX) family, in promoting CRC metastasis. The elevated expression of HOXA13 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in two independent CRC cohorts. Overexpression of HOXA13 promoted CRC metastasis whereas downregulation of HOXA13 suppressed CRC metastasis. Mechanistically, HOXA13 facilitated CRC metastasis by transactivating ATP-citrate lyase (ACLY) and insulin-like growth factor 1 receptor (IGF1R). Knockdown of ACLY and IGFIR inhibited HOXA13-medicated CRC metastasis, whereas ectopic overexpression of ACLY and IGFIR rescued the decreased CRC metastasis induced by HOXA13 knockdown. Furthermore, Insulin-like growth factor 1 (IGF1), the ligand of IGF1R, upregulated HOXA13 expression through the PI3K/AKT/HIF1α pathway. Knockdown of HOXA13 decreased IGF1-mediated CRC metastasis. In addition, the combined treatment of ACLY inhibitor ETC-1002 and IGF1R inhibitor Linsitinib dramatically suppressed HOXA13-mediated CRC metastasis. In conclusion, HOXA13 is a prognostic biomarker in CRC patients. Targeting the IGF1-HOXA13-IGF1R positive feedback loop may provide a potential therapeutic strategy for the treatment of HOXA13-driven CRC metastasis.

scholarly journals Farnesyl dimethyl chromanol targets colon cancer stem cells and prevents colorectal cancer metastasis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kazim Husain ◽  
Domenico Coppola ◽  
Chung S. Yang ◽  
Mokenge P. Malafa
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Metastasis ◽  
Annexin V ◽  
Cancer Cell Growth ◽  
Ki 67 ◽  
Sox2 Expression ◽  
Tumour Metastasis

AbstractThe activation and growth of tumour-initiating cells with stem-like properties in distant organs characterize colorectal cancer (CRC) growth and metastasis. Thus, inhibition of colon cancer stem cell (CCSC) growth holds promise for CRC growth and metastasis prevention. We and others have shown that farnesyl dimethyl chromanol (FDMC) inhibits cancer cell growth and induces apoptosis in vitro and in vivo. We provide the first demonstration that FDMC inhibits CCSC viability, survival, self-renewal (spheroid formation), pluripotent transcription factors (Nanog, Oct4, and Sox2) expression, organoids formation, and Wnt/β-catenin signalling, as evidenced by comparisons with vehicle-treated controls. In addition, FDMC inhibits CCSC migration, invasion, inflammation (NF-kB), angiogenesis (vascular endothelial growth factor, VEGF), and metastasis (MMP9), which are critical tumour metastasis processes. Moreover, FDMC induced apoptosis (TUNEL, Annexin V, cleaved caspase 3, and cleaved PARP) in CCSCs and CCSC-derived spheroids and organoids. Finally, in an orthotopic (cecum-injected CCSCs) xenograft metastasis model, we show that FDMC significantly retards CCSC-derived tumour growth (Ki-67); inhibits inflammation (NF-kB), angiogenesis (VEGF and CD31), and β-catenin signalling; and induces apoptosis (cleaved PARP) in tumour tissues and inhibits liver metastasis. In summary, our results demonstrate that FDMC inhibits the CCSC metastatic phenotype and thereby supports investigating its ability to prevent CRC metastases.

The Effect of High CDC6 Levels on Predicting Poor Prognosis in Colorectal Cancer

Chemotherapy ◽  
2022 ◽  
pp. 1-10
Author(s):  
Cheng Yang ◽  
Na Xie ◽  
Zhifei Luo ◽  
Xiling Ruan ◽  
Yixin Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Protein Expression ◽  
Poor Prognosis ◽  
Cancer Metastasis ◽  
Mrna Level ◽  
Normal Mucosa ◽  
Tnm Stage ◽  
Expression Levels ◽  
Normal Tissues

<b><i>Introduction:</i></b> We investigated the function of cell division cycle 6 (CDC6) on the prognosis in colorectal carcinoma (CRC). <b><i>Methods:</i></b> CDC6 protein expression levels in 121 patients with colorectal cancer and adjacent normal mucosa were detected by immunohistochemistry. <b><i>Results:</i></b> Compared to adjacent normal tissues, CDC6 mRNA level was overexpressed in CRC tissues. Moreover, CDC6 protein levels were expressed up to 93.39% (113/121) in CRC tissues in the cell nucleus or cytoplasm. However, there were only 5.79% (7/121) in normal mucosal tissues with nuclear expression. CDC6 expression was significantly correlated with TNM stage and tumor metastasis. The 5-year survival rate was lower in the high CDC6 expression group than the low group. After silencing of CDC6 expression in SW620 cells, cell proliferation was slowed, the tumor clones were decreased, and the cell cycle was arrested in G1 phase. In multivariate analysis, increased CDC6 protein expression levels in colon cancer tissues were associated with cancer metastasis, TNM stage, and patient survival time. <b><i>Conclusion:</i></b> CDC6 is highly expressed in CRC, and downregulation of CDC6 can slow the growth of CRC cells in vitro. It is also an independent predictor for poor prognosis and may be a useful biomarker for targeted therapy and prognostic evaluation.

Elevated expression of MGb2-Ag/TRAK1 is correlated with poor prognosis in patients with colorectal cancer

2011 ◽  
Vol 26 (11) ◽  
pp. 1397-1404 ◽  
Author(s):  
Yanxin An ◽  
Yi Zhou ◽  
Gui Ren ◽  
Qifei Tian ◽  
Yuanyuan Lu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Poor Prognosis ◽  
Elevated Expression

scholarly journals A novel class of inhibitors that target SRSF10 and promote p53-mediated cytotoxicity on human colorectal cancer cells

NAR Cancer ◽  
2021 ◽  
Vol 3 (2) ◽  
Author(s):  
Muhammad Sohail ◽  
Lulzim Shkreta ◽  
Johanne Toutant ◽  
Safwat Rabea ◽  
Jean-Philippe Babeu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Small Molecules ◽  
Human Colorectal Cancer ◽  
Independent Manner ◽  
Colorectal Cancer Cells ◽  
Elevated Expression ◽  
Splicing Regulator ◽  
Tumorigenic Activity ◽  
Human Colorectal Cancer Cells ◽  
Hct116 Cells

Abstract The elevated expression of the splicing regulator SRSF10 in metastatic colorectal cancer (CRC) stimulates the production of the pro-tumorigenic BCLAF1-L splice variant. We discovered a group of small molecules with an aminothiazole carboxamide core (GPS167, GPS192 and others) that decrease production of BCLAF1-L. While additional alternative splicing events regulated by SRSF10 are affected by GPS167/192 in HCT116 cells (e.g. in MDM4, WTAP, SLK1 and CLK1), other events are shifted in a SRSF10-independent manner (e.g. in MDM2, NAB2 and TRA2A). GPS167/192 increased the interaction of SRSF10 with the CLK1 and CLK4 kinases, leading us to show that GPS167/192 can inhibit CLK kinases preferentially impacting the activity of SRSF10. Notably, GPS167 impairs the growth of CRC cell lines and organoids, inhibits anchorage-independent colony formation, cell migration, and promotes cytoxicity in a manner that requires SRSF10 and p53. In contrast, GPS167 only minimally affects normal colonocytes and normal colorectal organoids. Thus, GPS167 reprograms the tumorigenic activity of SRSF10 in CRC cells to elicit p53-dependent apoptosis.

Elevated expression of KLK8 predicts poor prognosis in colorectal cancer

2017 ◽  
Vol 88 ◽  
pp. 595-602 ◽  
Author(s):  
Xianwu Liu ◽  
Bin Quan ◽  
Zhilong Tian ◽  
Hailin Xi ◽  
Gaolei Jia ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Poor Prognosis ◽  
Elevated Expression

Elevated expression of Thoc1 is associated with aggressive phenotype and poor prognosis in colorectal cancer

2015 ◽  
Vol 468 (1-2) ◽  
pp. 53-58 ◽  
Author(s):  
Chenchen Liu ◽  
Ben Yue ◽  
Chenwei Yuan ◽  
Senlin Zhao ◽  
Changyi Fang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Poor Prognosis ◽  
Aggressive Phenotype ◽  
Elevated Expression

scholarly journals Osteopontin Overexpression Induced Tumor Progression and Chemoresistance to Oxaliplatin through Induction of Stem-Like Properties in Human Colorectal Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Lui Ng ◽  
Timothy Wan ◽  
Ariel Chow ◽  
Deepak Iyer ◽  
Johnny Man ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cell ◽  
Poor Prognosis ◽  
Cancer Metastasis ◽  
Tumor Stage ◽  
Clinicopathological Parameters ◽  
Stem Cell Markers ◽  
Cell Markers ◽  
Response To Chemotherapy

Colorectal cancer (CRC) is one of the most common and fatal malignancies worldwide. The poor prognosis of colorectal cancer patients is due to development of chemoresistance and cancer metastasis. Recently osteopontin (OPN) has been associated with stem-like properties in colorectal cancer. This study further examined the clinicopathological significance of OPN in CRC and its effect on chemoresistance and transcription of stem cell markers. We examined the transcription level of OPN in 84 CRC patients and correlated the expression with their clinicopathological parameters. The associations of OPN overexpression with transcription of stem cell markers and response to chemotherapy in DLD1-OPN overexpressing clones and CRC patients were also investigated. Our results showed that OPN was significantly overexpressed in CRC, and its overexpression correlated with tumor stage and poor prognosis. Overexpression of CRC induced OCT4 and SOX2 expressionin vitroand correlated with SOX2 overexpression in CRC patients. In addition, DLD1-OPN overexpressing cells showed enhanced ability to survive upon oxaliplatin treatment, and OPN expression was higher in CRC patients who were resistant to oxaliplatin-involved chemotherapy treatment. Thus, CRC cells overexpressing OPN demonstrated stem-like properties and OPN inhibition is a potential therapeutic approach to combat CRC progression and chemoresistance.

scholarly journals Clinical positioning of the IAP antagonist tolinapant (ASTX660) in colorectal cancer

2020 ◽  
Author(s):  
Nyree Crawford ◽  
Katie Stott ◽  
Tamas Sessler ◽  
Christopher McCann ◽  
William McDaid ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Histone Deacetylases ◽  
Poor Prognosis ◽  
Standard Of Care ◽  
Class I ◽  
Caspase 8 ◽  
Iap Antagonist ◽  
Elevated Expression ◽  
Folfox Chemotherapy ◽  
Induced Apoptosis

AbstractCancer cells frequently express elevated levels of Inhibitor of Apoptosis Proteins (IAPs): cIAPI, cIAP2 and XIAP. Elevated expression of cIAP1 and cIAP2 (but not XIAP) significantly correlated with poor prognosis in microsatellite stable (MSS) stage-III colorectal cancer (CRC) patients treated with adjuvant chemotherapy, suggesting their involvement in promoting resistance. Preclinical analysis of the IAP inhibitor tolinapant in CRC cell lines demonstrated robust on-target effects and caspase-8-dependent apoptosis that was inhibited by the caspase-8 paralogs FLIP and, unexpectedly, caspase-10. Importantly, tolinipant-induced apoptosis was augmented by standard-of-care chemotherapy (FOLFOX) in CRC disease models, due (at least in part) to FOLFOX-induced downregulation of Class-I histone deacetylases, leading to acetylation of the FLIP-binding partner Ku70 and downregulation of FLIP. Moreover, this effect could be phenocopied using a Class-I HDAC inhibitor. Further analyses revealed that caspase-8-knockout RIPK3-positive CRC models were sensitive to tolinostat-induced necroptosis, an effect that could be exploited with the FDA-approved caspase inhibitor emricasan. Our study provides evidence for immediate clinical exploration of tolinapant in combination with FOLFOX chemotherapy in poor prognosis MSS CRC with elevated cIAP1/2 expression.

scholarly journals Poor prognosis of stage I lung adenocarcinoma patients determined by elevated expression over pre/minimally invasive status of COL11A1 and THBS2 in the focal adhesion pathway

2021 ◽  
Author(s):  
Jun Shang ◽  
Yue Zhao ◽  
He Jiang ◽  
Jingcheng Yang ◽  
Naixin Zhang ◽  
...  
Keyword(s):  
Minimally Invasive ◽  
Lung Adenocarcinoma ◽  
Focal Adhesion ◽  
Poor Prognosis ◽  
Stage I ◽  
Molecular Characteristics ◽  
Data Sets ◽  
External Data ◽  
Post Surgery ◽  
Elevated Expression

Around 20% stage I lung adenocarcinoma (LUAD) patients die within five years after surgery, and efforts for developing gene-expression based models for risk-tailored post-surgery treatment are largely unsatisfactory due to overfitting-related lack of validation and extrapolation. Because patients with adenocarcinomas in situ (AIS) and minimally invasive (MIA) LUAD are completely curable by surgical resection, we hypothesize that poor-prognosis stage I patients may exhibit key molecular characteristics deviating from AIS/MIA. We first found focal adhesion (FA) as the only pathway significantly perturbed at both genomic and transcriptomic levels by comparing 98 AIS/MIA and 99 invasive LUAD patients. Then, we identified two FA pathway genes (COL11A1 and THBS2) strongly upregulated from AIS/MIA to stage I while expressed steadily from normal to AIS/MIA. Furthermore, unsupervised clustering separated stage I patients into two molecularly and prognostically distinct subtypes (S1 and S2) based solely on the expression levels of COL11A1 and THBS2 (FA2). Subtype S1 looked like AIS/MIA, whereas S2 exhibited more somatic alterations, elevated expression of COL11A1 and THBS2, and more activated cancer-associated fibroblast (CAF). The prognostic performance of the knowledge-driven and overfitting-resistant FA2 model was validated with 12 external data sets and may help reliably identify high-risk stage I patients for more intensive post-surgery treatment.

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