Primary Cilium in Cancer Hallmarks

Abstract

The primary cilium is a solitary, nonmotile and transitory appendage that is present in virtually all mammalian cells. Our knowledge of its ultrastructure and function is the result of more than fifty years of research that has dramatically changed our perspectives on the primary cilium. The mutual regulation between ciliogenesis and the cell cycle is now well-recognized, as well as the function of the primary cilium as a cellular “antenna” for perceiving external stimuli, such as light, odorants, and fluids. By displaying receptors and signaling molecules, the primary cilium is also a key coordinator of signaling pathways that converts extracellular cues into cellular responses. Given its critical tasks, any defects in primary cilium formation or function lead to a wide spectrum of diseases collectively called “ciliopathies”. An emerging role of primary cilium is in the regulation of cancer development. In this review, we seek to describe the current knowledge about the influence of the primary cilium in cancer progression, with a focus on some of the events that cancers need to face to sustain survival and growth in hypoxic microenvironment: the cancer hallmarks.

Ciliary Genes in Renal Cystic Diseases

“…The loss of cilia in the kidney releases basal bodies and provokes inappropriate cell division, aberrant Wnt, Hedgehog or PDGF signaling and overproliferation. Finally, strong evidence suggests that cilia have tumor suppressive effects controlling signaling pathways associated with tumorigenesis [148,149]. A recent study in mice triple mutant of tumor suppressors Vhl, Trp53 and Rb1 resulting in development of renal cancer, showed enrichment in ciliary genes mutations [147].…”

<p>Cbl Proto-Oncogene B (CBLB) c.197A>T Mutation Induces Mild Metabolic Dysfunction in Partial Type I Multiple Symmetric Lipomatosis (MSL)</p>

“…CBLB is a critical factor in the promotion of proteosome-mediated protein degradation and extensively participates in the host immune response, insulin resistance, inflammation, allergies, and cancer development. 23,50,51 CBLB is a highly evolutionary conversation protein from the nematodes to the vertebrates, 23,52 and the CBLB p.Q66L mutation is localized in the region of the TKB domain that binds to the tyrosine site of protein phosphorylation and ubiquitinates the target proteins. In our current study, we found that this point mutation was highly conserved in 98 vertebrates using the UCSC tool, and our bioinformatical analysis identified a very low mutation frequency that could be harmful if it occurred in the CBLB p.Q66L site.…”

Targeting E3 Ubiquitin Ligases and Deubiquitinases in Ciliopathy and Cancer

“…Importantly, forced ciliation in cells growing under serum stimulation conditions can cause cell-cycle arrest [ 33 , 34 , 101 , 102 , 106 ]. These findings suggest that the primary cilium can act as a negative regulator of the cell cycle and may be a tumor suppressor organelle [ 3 , 4 , 5 , 6 , 9 , 107 , 108 , 109 ]. In fact, the suppression of primary cilia function is associated with tumorigenesis, cell proliferation, and metastasis in many cancers, including glioblastoma [ 110 ], esophageal cancer [ 111 ], colon cancer [ 112 ], cholangiocarcinoma [ 113 , 114 ], pancreatic ductal adenocarcinoma [ 115 ], clear cell renal carcinoma [ 116 ], prostate cancer [ 117 ], ovarian cancer [ 118 , 119 ], melanoma [ 120 ], and chondrosarcoma [ 121 ] ( Table 2 ).…”

“…CRL2 VHL ubiquitinates the α subunit of the transcription factor hypoxia-inducible factor 1 (HIF1α), leading to its proteasomal degradation [ 138 , 153 ]. VHL and HIF1α positively and negatively, respectively, regulate ciliogenesis and cancer [ 107 , 139 , 140 , 154 ].…”