Role of Regulatory Oncogenic or Tumor Suppressor miRNAs of PI3K/AKT Signaling Axis in the Pathogenesis of Colorectal Cancer

2019 ◽  
Vol 24 (39) ◽  
pp. 4605-4610 ◽  
Author(s):  
Atena Soleimani ◽  
Farzad Rahmani ◽  
Gordon A. Ferns ◽  
Mikhail Ryzhikov ◽  
Amir Avan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Current Knowledge ◽  
Akt Signaling ◽  
Tumor Tissues ◽  
Radio Therapy ◽  
Signaling Axis ◽  
Cancer Tumor ◽  
Novel Biomarkers

Colorectal cancer (CRC) is the leading cause of cancer death worldwide and its incidence is increasing. In most patients with CRC, the PI3K/AKT signaling axis is over-activated. Regulatory oncogenic or tumor suppressor microRNAs (miRNAs) for PI3K/AKT signaling regulate cell proliferation, migration, invasion, angiogenesis, as well as resistance to chemo-/radio-therapy in colorectal cancer tumor tissues. Thus, regulatory miRNAs of PI3K/AKT/mTOR signaling represent novel biomarkers for new patient diagnosis and obtaining clinically invaluable information from post-treatment CRC patients for improving therapeutic strategies. This review summarizes the current knowledge of miRNAs’ regulatory roles of PI3K/AKT signaling in CRC pathogenesis.

scholarly journals Chemokines—What Is Their Role in Colorectal Cancer?

2020 ◽  
Vol 27 (1) ◽  
pp. 107327482090338 ◽  
Author(s):  
Sara Pączek ◽  
Marta Łukaszewicz-Zając ◽  
Barbara Mroczko
Keyword(s):  
Colorectal Cancer ◽  
Current Knowledge ◽  
Early Stage ◽  
Distant Metastases ◽  
Cell Types ◽  
Diagnosis And Prognosis ◽  
Novel Biomarkers ◽  
Specific Receptors ◽  
Common Malignancy

Colorectal cancer (CRC) is one of the leading causes of cancer-related death. It is the second most frequently diagnosed malignancy in Europe and third worldwide. Colorectal malignancies diagnosed at an early stage offer a promising survival rate. However, advanced tumors often present distant metastases even after the complete resection of a primary tumor. Therefore, novel biomarkers of CRC are sorely needed in the diagnosis and prognosis of this common malignancy. A family of chemokines are composed of small, secreted proteins. They are best known for their ability to stimulate the migration of several cell types. Some investigations have indicated that chemokines are involved in cancer development, including CRC. This article presents current knowledge regarding chemokines and their specific receptors in CRC progression. Moreover, the prime aim of this review is to summarize the potential role of these proteins as biomarkers in the diagnosis and prognosis of CRC.

scholarly journals Tribbles Pseudokinases in Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2825
Author(s):  
Bibiana I. Ferreira ◽  
Bruno Santos ◽  
Wolfgang Link ◽  
Ana Luísa De Sousa-Coelho
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Protein Expression ◽  
Tumor Suppressor Genes ◽  
Current Knowledge ◽  
Pharmacological Modulation ◽  
Cellular Processes ◽  
Gene And Protein Expression ◽  
Potential Biomarkers

The Tribbles family of pseudokinases controls a wide number of processes during cancer on-set and progression. However, the exact contribution of each of the three family members is still to be defined. Their function appears to be context-dependent as they can act as oncogenes or tumor suppressor genes. They act as scaffolds modulating the activity of several signaling pathways involved in different cellular processes. In this review, we discuss the state-of-knowledge for TRIB1, TRIB2 and TRIB3 in the development and progression of colorectal cancer. We take a perspective look at the role of Tribbles proteins as potential biomarkers and therapeutic targets. Specifically, we chronologically systematized all available articles since 2003 until 2020, for which Tribbles were associated with colorectal cancer human samples or cell lines. Herein, we discuss: (1) Tribbles amplification and overexpression; (2) the clinical significance of Tribbles overexpression; (3) upstream Tribbles gene and protein expression regulation; (4) Tribbles pharmacological modulation; (5) genetic modulation of Tribbles; and (6) downstream mechanisms regulated by Tribbles; establishing a comprehensive timeline, essential to better consolidate the current knowledge of Tribbles’ role in colorectal cancer.

scholarly journals KLF2 Inhibits the Migration and Invasion of Prostate Cancer Cells by Downregulating MMP2

2018 ◽  
Vol 13 (1) ◽  
pp. 155798831881690 ◽  
Author(s):  
Binshuai Wang ◽  
Mingyuan Liu ◽  
Yimeng Song ◽  
Changying Li ◽  
Shudong Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Cell Function ◽  
Malignant Tumors ◽  
Suppressor Gene ◽  
Migration And Invasion ◽  
Tissue Samples ◽  
Tumor Tissues ◽  
Luciferase Activity Assay

KLF2, a member of the Kruppel-like factor (KLF) family, is thought to be a tumor suppressor in many kinds of malignant tumors. Its functions in prostate cancer (PCa) are unknown. This study aimed to explore the role of KLF2 in the migration and invasion of PCa cells. The expression of KLF2 was measured by immunohistochemistry in PCa tissues and in paired non-tumor tissues. KLF2 and MMP2 expression in cells was measured by Western blot and RT-qPCR. Adenoviruses and siRNAs were used in cell function tests to investigate the role of KLF2 in regulating MMP2. Interactions between KLF2 and MMP2 were analyzed by a luciferase activity assay. The present study, for the first time, identified that KLF2 was downregulated both in PCa clinical tissue samples and in cancer cell lines. The overexpression of KLF2 inhibited the migration and invasion of PCa cells via the suppression of MMP2.This study demonstrates that KLF2 might act as a tumor suppressor gene in PCa and that the pharmaceutical upregulation of KLF2 may be a potential approach for treatment.

scholarly journals Paradoxical Role of HMGB1 in Pancreatic Cancer: Tumor Suppressor or Tumor Promoter?

2016 ◽  
Vol 36 (9) ◽  
pp. 4381-4390 ◽  
Author(s):  
MARÍA JOSÉ GARCÍA CEBRIÁN ◽  
MONIKA BAUDEN ◽  
ROLAND ANDERSSON ◽  
STEFAN HOLDENRIEDER ◽  
DANIEL ANSARI
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Suppressor ◽  
Tumor Promoter ◽  
Cancer Tumor

scholarly journals Extracellular Chaperones as Novel Biomarkers of Overall Cancer Progression and Efficacy of Anticancer Therapy

2020 ◽  
Vol 10 (17) ◽  
pp. 6009
Author(s):  
Malgorzata Anna Krawczyk ◽  
Agata Pospieszynska ◽  
Małgorzata Styczewska ◽  
Ewa Bien ◽  
Sambor Sawicki ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Current Knowledge ◽  
Therapeutic Targets ◽  
Age Group ◽  
Cancer Management ◽  
Novel Biomarkers ◽  
Immune System Regulation ◽  
New Biomarkers ◽  
Shock Proteins

Exosomal heat shock proteins (Hsps) are involved in intercellular communication both in physiological and pathological conditions. They play a role in key processes of carcinogenesis including immune system regulation, cell differentiation, vascular homeostasis and metastasis formation. Thus, exosomal Hsps are emerging biomarkers of malignancies and possible therapeutic targets. Adolescents and young adults (AYAs) are patients aged 15–39 years. This age group, placed between pediatric and adult oncology, pose a particular challenge for cancer management. New biomarkers of cancer growth and progression as well as prognostic factors are desperately needed in AYAs. In this review, we attempted to summarize the current knowledge on the role of exosomal Hsps in selected solid tumors characteristic for the AYA population and/or associated with poor prognosis in this age group. These included malignant melanoma, brain tumors, and breast, colorectal, thyroid, hepatocellular, lung and gynecological tract carcinomas. The studies on exosomal Hsps in these tumors are limited; however; some have provided promising results. Although further research is needed, there is potential for future clinical applications of exosomal Hsps in AYA cancers, both as novel biomarkers of disease presence, progression or relapse, or as therapeutic targets or tools for drug delivery.

scholarly journals Unveiling role of sphingosine-1-phosphate receptor 2 as a brake of epithelial stem cell proliferation and a tumor suppressor in colorectal cancer

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Luciana Petti ◽  
Giulia Rizzo ◽  
Federica Rubbino ◽  
Sudharshan Elangovan ◽  
Piergiuseppe Colombo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Tumor Suppressor ◽  
Normal Mucosa ◽  
Intestinal Stem Cells ◽  
Intestinal Epithelial ◽  
Sphingosine 1 Phosphate

Abstract Background Sphingosine-1-phosphate receptor 2 (S1PR2) mediates pleiotropic functions encompassing cell proliferation, survival, and migration, which become collectively de-regulated in cancer. Information on whether S1PR2 participates in colorectal carcinogenesis/cancer is scanty, and we set out to fill the gap. Methods We screened expression changes of S1PR2 in human CRC and matched normal mucosa specimens [N = 76]. We compared CRC arising in inflammation-driven and genetically engineered models in wild-type (S1PR2+/+) and S1PR2 deficient (S1PR2−/−) mice. We reconstituted S1PR2 expression in RKO cells and assessed their growth in xenografts. Functionally, we mimicked the ablation of S1PR2 in normal mucosa by treating S1PR2+/+ organoids with JTE013 and characterized intestinal epithelial stem cells isolated from S1PR2−/−Lgr5-EGFP- mice. Results S1PR2 expression was lost in 33% of CRC; in 55%, it was significantly decreased, only 12% retaining expression comparable to normal mucosa. Both colitis-induced and genetic Apc+/min mouse models of CRC showed a higher incidence in size and number of carcinomas and/or high-grade adenomas, with increased cell proliferation in S1PR2−/− mice compared to S1PR2+/+ controls. Loss of S1PR2 impaired mucosal regeneration, ultimately promoting the expansion of intestinal stem cells. Whereas its overexpression attenuated cell cycle progression, it reduced the phosphorylation of AKT and augmented the levels of PTEN. Conclusions In normal colonic crypts, S1PR2 gains expression along with intestinal epithelial cells differentiation, but not in intestinal stem cells, and contrasts intestinal tumorigenesis by promoting epithelial differentiation, preventing the expansion of stem cells and braking their malignant transformation. Targeting of S1PR2 may be of therapeutic benefit for CRC expressing high Lgr5. Graphical Abstract. Schematic drawing of the role of S1PR2 in normal mucosa and colorectal cancer. In the normal mucosa, S1PR2 is highly expressed by differentiated cells at the upper region of both colon and intestinal crypts (S1PR2 ON), but not by the undifferentiated stem cell at the base of the crypts (S1PR2 OFF), in which acts as a negative proliferative regulator promoting epithelial differentiation. Its loss leads to the expansion of stem cells and reduced levels of PTEN and Axin-2, two negative regulators respectively of PI3K/AKT and Wnt signaling that control β-catenin signaling. The translocation of β-catenin into the nucleus promotes the transcription of target genes involved in the proliferation and malignant transformation. Thereby, S1PR2 works in the intestine as a tumor suppressor

The Role of Mir-150 as a Tumor Suppressor In Malignant Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 465-465
Author(s):  
Atsushi Watanabe, ◽  
Hiroyuki Tagawa ◽  
Kazuaki Teshima ◽  
Yoshihiro Kameoka ◽  
Naoto Takahashi ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
Telomerase Activity ◽  
Akt Signaling ◽  
T Cell Lymphoma ◽  
Nk T Cell

Abstract Abstract 465 Disease specific genetic alteration or translocation have not been identified in NK/T cell lymphoma. We recently demonstrated that over expressions of miR-21 and/or miR-155 are frequently occurring in natural killer (NK) cell lymphoma/leukemia and deeply associated with their lymphomagenesis by deregulation of AKT signaling. In this study, we tried to identify tumor suppressor miRNA(s) in malignant lymphomas including B-cell, NK-cell and CD4+T-cell lymphoma, by using quantitative PCR and/or Northern blot analysis. We found that miR-150 in both cell lines and primary samples of NK and T-cell lymphoma showed significantly lower expression than those of normal natural killer cells and CD4+T cells. To examine the role for lymphomagenesis, we stably transduced miR-150 into lymphoma cell lines. Enforced expression of miR-150 in NK/T cell lymphoma cell lines showed increased levels of susceptibility of apoptosis, and showed senescence with reduced levels of telomerase activity and telomere DNA shortening. We further demonstrated that miR-150 directly down regulate AKT2, leading to reduced expression of phosphorylated AKTser473/474 with upregulation of tumor suppressors, Bim, p27 and p53. Since it has been proven that AKT kinase phosphorylate hTERT (human telomerase reverse transcript), downregulation of miR-150 in lymphomas lead to activate telomerase activity, resulting immortalization of the cancer cells. These results suggest that miR-150 play as a role of tumor suppressor in NK/T-cell lymphoma. Our recent and previous report demonstrate that downregulation of miR-150 and upregulation of miR-21/miR-155 collaborately contribute to NK/T-cell lymphomagenesis by deregulating AKT signaling. These findings will give a new insight into the pathogenesis of NK/T cell lymphoma and the miR-150 itself and/or AKT targeting therapy can be a useful against aggressive lymphoma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The critical role and potential target of the autotaxin/lysophosphatidate axis in pancreatic cancer

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769454 ◽  
Author(s):  
Ming Quan ◽  
Jiu-jie Cui ◽  
Xiao Feng ◽  
Qian Huang
Keyword(s):  
Pancreatic Cancer ◽  
Current Knowledge ◽  
Critical Role ◽  
Treatment Resistance ◽  
G Protein Coupled Receptors ◽  
Signaling Axis ◽  
Tumorigenesis And Progression ◽  
Pathologic Processes ◽  
G Protein Coupled

Autotaxin, an ecto-lysophospholipase D encoded by the human ENNP2 gene, is expressed in multiple tissues, and participates in numerous critical physiologic and pathologic processes including inflammation, pain, obesity, embryo development, and cancer via the generation of the bioactive lipid lysophosphatidate. Overwhelming evidences indicate that the autotaxin/lysophosphatidate signaling axis serves key roles in the numerous processes central to tumorigenesis and progression, including proliferation, survival, migration, invasion, metastasis, cancer stem cell, tumor microenvironment, and treatment resistance by interacting with a series of at least six G-protein-coupled receptors (LPAR1–6). This review provides an overview of the autotaxin/lysophosphatidate axis and collates current knowledge regarding its specific role in pancreatic cancer. With a deeper understanding of the critical role of the autotaxin/lysophosphatidate axis in pancreatic cancer, targeting autotaxin or lysophosphatidate receptor may be a potential and promising strategy for cancer therapy.

scholarly journals The Role of the Tumor Suppressor Gene Protein Tyrosine Phosphatase Gamma in Cancer

2022 ◽  
Vol 9 ◽  
Author(s):  
Christian Boni ◽  
Claudio Sorio
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Protein Tyrosine Phosphatase ◽  
Growth Regulation ◽  
Current Knowledge ◽  
Tyrosine Phosphatase ◽  
Suppressor Gene ◽  
Missense Mutations ◽  
Protein Tyrosine

Members of the Protein Tyrosine Phosphatase (PTPs) family are associated with growth regulation and cancer development. Acting as natural counterpart of tyrosine kinases (TKs), mainly involved in crucial signaling pathways such as regulation of cell cycle, proliferation, invasion and angiogenesis, they represent key parts of complex physiological homeostatic mechanisms. Protein tyrosine phosphatase gamma (PTPRG) is classified as a R5 of the receptor type (RPTPs) subfamily and is broadly expressed in various isoforms in different tissues. PTPRG is considered a tumor-suppressor gene (TSG) mapped on chromosome 3p14-21, a region frequently subject to loss of heterozygosity in various tumors. However, reported mechanisms of PTPRG downregulation include missense mutations, ncRNA gene regulation and epigenetic silencing by hypermethylation of CpG sites on promoter region causing loss of function of the gene product. Inactive forms or total loss of PTPRG protein have been described in sporadic and Lynch syndrome colorectal cancer, nasopharyngeal carcinoma, ovarian, breast, and lung cancers, gastric cancer or diseases affecting the hematopoietic compartment as Lymphoma and Leukemia. Noteworthy, in Central Nervous System (CNS) PTPRZ/PTPRG appears to be crucial in maintaining glioblastoma cell-related neuronal stemness, carving out a pathological functional role also in this tissue. In this review, we will summarize the current knowledge on the role of PTPRG in various human cancers.

scholarly journals Restoration of miR-193a-5p and miR-146 a-5p Expression Induces G1 Arrest in Colorectal Cancer through Targeting of MDM2/p53

2019 ◽  
Vol 10 (1) ◽  
pp. 130-134 ◽  
Author(s):  
Saeed Noorolyai ◽  
Elham Baghbani ◽  
Leili Aghebati Maleki ◽  
Amir Baghbanzadeh Kojabad ◽  
Dariush Shanehbansdi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Cycle Progression ◽  
Cyclin B ◽  
G1 Arrest ◽  
Cycle Progression ◽  
Ht 29

Purpose: Colorectal cancer (CRC) remains a universal and lethal cancer owing to metastatic and relapsing disease. Currently, the role of microRNAs has been checked in tumorigeneses. Numerous studies have revealed that between the tumor suppressor miRNAs, the reduced expression of miR-146a-5p and -193a-5p in several cancers including CRC tissues are related with tumor progression and poor prognosis of patients. The purpose of this study is to examine the role of miR-146 a-5p and -193 a-5p in CRC cell cycle progression. Methods: The miR-193a-5p and -146 a-5p mimics were transfected into HT-29 CRC cells via jetPEI transfection reagent and their impact was assessed on p53, cyclin B, and NF-kB gene expression. The inhibitory effect of these miRNAs on cell cycle was assessed by flow cytometry. The consequence of miR-193a-5p and miR-146 a-5p on the protein expression level of Murine double minute 2 (MDM2) was assessed by western blotting. Results: miR193a-5p and -146a-5p regulated the expression of MDM2 protein and p53, cyclin B, and NF-kB gene expression in CRC cells. Treatment of HT-29 cells with miRNA-146a-5p and -193a-5p induced G1 cell cycle arrest. Conclusion: The findings of our study suggest that miR146a-5p and -193a-5p may act as a potential tumor suppressor by their influence on cell cycle progression in CRC cells. Thus, miRNA-146a-5p and -193a-5p restoration may be recommended as a potential therapeutic goal in the treatment of CRC patients.

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