scholarly journals Identification of ZBTB18 as a novel colorectal tumor suppressor gene through genome-wide promoter hypermethylation analysis

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Sarah Bazzocco ◽  
Higinio Dopeso ◽  
Águeda Martínez-Barriocanal ◽  
Estefanía Anguita ◽  
Rocío Nieto ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Promoter Methylation ◽  
Advanced Colorectal Cancer ◽  
Locally Advanced ◽  
Promoter Hypermethylation ◽  
Genome Wide ◽  
Colorectal Cancer Cell Lines ◽  
Locally Advanced Colorectal Cancer

Abstract Background Cancer initiation and progression are driven by genetic and epigenetic changes. Although genome/exome sequencing has significantly contributed to the characterization of the genetic driver alterations, further investigation is required to systematically identify cancer driver genes regulated by promoter hypermethylation. Results Using genome-wide analysis of promoter methylation in 45 colorectal cancer cell lines, we found that higher overall methylation levels were associated with microsatellite instability (MSI), faster proliferation and absence of APC mutations. Because epigenetically silenced genes could represent important oncogenic drivers, we used mRNA expression profiling of colorectal cancer cell lines and primary tumors to identify a subset of 382 (3.9%) genes for which promoter methylation was negatively associated with gene expression. Remarkably, a significant enrichment in zinc finger proteins was observed, including the transcriptional repressor ZBTB18. Re-introduction of ZBTB18 in colon cancer cells significantly reduced proliferation in vitro and in a subcutaneous xenograft mouse model. Moreover, immunohistochemical analysis revealed that ZBTB18 is frequently lost or reduced in colorectal tumors, and reduced ZBTB18 expression was found to be associated with lymph node metastasis and shorter survival of patients with locally advanced colorectal cancer. Conclusions We identified a set of 382 genes putatively silenced by promoter methylation in colorectal cancer that could significantly contribute to the oncogenic process. Moreover, as a proof of concept, we demonstrate that the epigenetically silenced gene ZBTB18 has tumor suppressor activity and is a novel prognostic marker for patients with locally advanced colorectal cancer.

EXPERIENCE OF THE APPLICATION OF THERMOCHEMIORRADIOTHERAPY IN COMBINED TREATMENT OF DYSTAL CANCER OF DIRECT INTESTINE

2019 ◽  
Vol 65 (1) ◽  
pp. 131-134
Author(s):  
Zhanna Startseva ◽  
Sergey Afanasev ◽  
Dina Plaskeeva
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Primary Tumor ◽  
Advanced Colorectal Cancer ◽  
Combined Treatment ◽  
Locally Advanced ◽  
Chemoradiation Therapy ◽  
Locally Advanced Colorectal Cancer

The article describes the experience of using ther-mochioradiotherapy in the combined treatment of distal locally advanced colorectal cancer, as well as comparing the effectiveness of treatment with chemoradiation therapy. The use of the proposed method as a component of the combined treatment of patients with rectal cancer allowed to increase the percentage of organ-preserving operations. As a result of thermochemotherapy, the prevalence of the primary tumor was significantly reduced, as a result of which the number of sphincter-bearing operations was reduced by almost 2 times (p

Extended resections are beneficial for patients with locally advanced colorectal cancer

1995 ◽  
Vol 38 (12) ◽  
pp. 1251-1256 ◽  
Author(s):  
J. R. Izbicki ◽  
S. B. Hosch ◽  
W. T. Knoefel ◽  
B. Passlick ◽  
C. Bloechle ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Advanced Colorectal Cancer ◽  
Locally Advanced ◽  
Locally Advanced Colorectal Cancer

scholarly journals First-line treatment with modified FOLFOXIRI plus bevacizumab in patients with locally advanced colorectal cancer

2020 ◽  
Vol 28 (1) ◽  
pp. 44-48 ◽  
Author(s):  
Yasufumi Yamada ◽  
Kazuhiko Yoshimatsu ◽  
Hajime Yokomizo ◽  
Sachiyo Okayama ◽  
Hiroyuki Maeda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Advanced Colorectal Cancer ◽  
Locally Advanced ◽  
Line Treatment ◽  
First Line ◽  
Locally Advanced Colorectal Cancer ◽  
First Line Treatment

scholarly journals MiR-382 functions as tumor suppressor and chemosensitizer in colorectal cancer

2019 ◽  
Vol 39 (8) ◽  
Author(s):  
Hui Yao ◽  
Dong Xia ◽  
Zong-lin Li ◽  
Lei Ren ◽  
Ming-ming Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Cancer Cell ◽  
Critical Role ◽  
Colorectal Cancer Cell ◽  
Cancer Cell Proliferation ◽  
Interacting Protein ◽  
Colorectal Cancer Cell Lines ◽  
Cancer Tissues

Abstract Increasing evidence suggests that microRNAs (miRNAs) play a critical role in tumorigenesis. Decreased expression of miR-382 has been observed in various types of cancers. However, the biological function of miR-382 in colorectal cancer (CRC) is still largely unknown. Here, we found that miR-382 was down-regulated in human colorectal cancer tissues and cell lines associated with it. MiR-382 inhibited colorectal cancer cell proliferation, migration, invasion, and enhance chemosensitivity. Furthermore, we identified Krüppel-like factor 12 (KLF12) and homeodomain-interacting protein kinase 3 (HIPK3) as the target of miR-382, and miR-382 rescued the promotion effect of KFL12 on migration and enhanced chemosensitivity in colorectal cancer cell lines. Collectively, these findings revealed that miR-382 inhibits migration and enhances chemosensitivity by targeting KLF12 and HIPK3 in colorectal cancer. These findings might serve as a tumor suppressor in CRC.

scholarly journals Targeting Acid Ceramidase to Improve the Radiosensitivity of Rectal Cancer

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2693
Author(s):  
Rachael E. Clifford ◽  
Naren Govindarajah ◽  
David Bowden ◽  
Paul Sutton ◽  
Mark Glenn ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Locally Advanced ◽  
Advanced Rectal Cancer ◽  
Cancer Cell Lines ◽  
Locally Advanced Rectal Cancer ◽  
Colorectal Cancer Cell ◽  
Colorectal Cancer Cell Lines

Previous work utilizing proteomic and immunohistochemical analyses has identified that high levels of acid ceramidase (AC) expression confers a poorer response to neoadjuvant treatment in locally advanced rectal cancer. We aimed to assess the radiosensitising effect of biological and pharmacological manipulation of AC and elucidate the underlying mechanism. AC manipulation in three colorectal cancer cell lines (HT29, HCT116 and LIM1215) was achieved using siRNA and plasmid overexpression. Carmofur and a novel small molecular inhibitor (LCL521) were used as pharmacological AC inhibitors. Using clonogenic assays, we demonstrate that an siRNA knockdown of AC enhanced X-ray radiosensitivity across all colorectal cancer cell lines compared to a non-targeting control siRNA, and conversely, AC protein overexpression increased radioresistance. Using CRISPR gene editing, we also generated AC knockout HCT116 cells that were significantly more radiosensitive compared to AC-expressing cells. Similarly, two patient-derived organoid models containing relatively low AC expression were found to be comparatively more radiosensitive than three other models containing higher levels of AC. Additionally, AC inhibition using carmofur and LCL521 in three colorectal cancer cell lines increased cellular radiosensitivity. Decreased AC protein led to significant poly-ADP ribose polymerase-1 (PARP-1) cleavage and apoptosis post-irradiation, which was shown to be executed through a p53-dependent process. Our study demonstrates that expression of AC within colorectal cancer cell lines modulates the cellular response to radiation, and particularly that AC inhibition leads to significantly enhanced radiosensitivity through an elevation in apoptosis. This work further solidifies AC as a target for improving radiotherapy treatment of locally advanced rectal cancer.

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