Abstract
Simple SummaryThe 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 functions appear 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.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.
Highlights
Colorectal cancer (CRC) refers to a malignant tumor that arises from the colon or rectum epithelium
There has been accumulating evidence that all members of the Tribbles family play a role in tumorigenesis
This is not as clear for TRIB3, as it was found that TRIB3 overexpression negatively regulates the mTOR pathway, which is hyperactivated in several tumor types
Summary
Colorectal cancer (CRC) refers to a malignant tumor that arises from the colon or rectum epithelium. They are often referred together due to their many features in common. In the adenoma–carcinoma pathway, CRC evolves from non-malignant precursor lesions called adenomas, for a period of at least 10 years [4] This process begins with the activation of Wnt signaling due to the loss of the tumor suppressor APC (Adenomatous polyposis coli) through inactivating mutations. RAS-BRAF wild type CRC is associated with resistance to anti-EGFR treatment in the presence of high c-MYC levels [13,14,15,16]. Fbilruset afluatgh)o.rFliarst naaumtheoirslsahsot wnanmfoeriesaschhoflwang.foArteoatachl of four articles studying or including TRIB1, five for TRIB2, and 14 for TRIB3, in colon cancer, were identified from 2003 to 2020 and are included in the review
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