HuR Regulates β-Tubulin Isotype Expression in Ovarian Cancer

Abstract

The supply of oxygen and nutrients to solid tumors is inefficient because cancer tissues have an inadequate number of microvessels, thus inducing the selective growth of the most aggressive cancer cells. This explains why many of the factors underlying a poor prognosis are induced in hypoxic/hypoglycemic conditions. Among these factors, a prominent role in several solid tumors is played by the class III β-tubulin gene (TUBB3). The study described here reveals that glucose deprivation enhances TUBB3 expression at both the gene and protein levels in A2780 ovarian cancer cells. In silico analysis of TUBB3 mRNA sequence predicted a putative binding site for the RNA-binding protein Hu antigen (HuR) in the 3′ flanking untranslated region. A hypoglycemic-dependent engagement of this site was shown using RNA pull-down and ribonucleoimmunoprecipitation techniques. Thereafter, HuR gene silencing revealed that TUBB3 translation is HuR dependent in hypoglycemia because HuR silencing inhibited the entry of TUBB3 mRNA into cytoskeletal and free polysomes. Finally, the clinical value of this finding was assessed in a clinical cohort of 46 ovarian cancer patients in whom it was found that HuR cytoplasmic staining was associated with high levels of TUBB3 and poor survival. CancerRes; 70(14); 5891-900. ©2010 AACR.

Gender Influences the Class III and V β-Tubulin Ability to Predict Poor Outcome in Colorectal Cancer

“…In females the expression of both TUBB3 HuR and TUBB6 was higher in patients with metastatic disease. Therefore in females, the same pathway that we previously reported in ovarian cancer (6,15,19) is implicated. On the other hand, if these 2 biomarkers are not expressed, the disease seems less aggressive and the outcome better.…”

“…To our knowledge this is the first article addressing the role of TUBB3 in colorectal cancer. Recent findings support the notion that the TUBB3 pathway is an adaptive response to exposure to microenvironmental stressors, such as hypoxia and poor nutrient supply (5,6). For this reason TUBB3 is a biomarker of biologic aggressiveness and the tendency toward metastasis (7).…”

“…Although originally identified as a mechanism of drug resistance to taxanes (4), recent studies have shown that TUBB3 is involved in an adaptive response to low oxygen levels and poor nutrient supply in a growing number of solid tumors (5,6). This explains the involvement of TUBB3 in drug resistance independent of whether the disease is treated with a regimen that includes a microtubule targeting agent or not (7).…”

HGF/c-Met axis drives cancer aggressiveness in the neoadjuvant setting of ovarian cancer

“…These findings together support the potential clinical utility in the refractory NACT setting (exhibiting high HGF (protein/gene) and low MET gene high c-Met protein) of the inhibition of both c-Met and HGF. It has been demonstrated that a block of translation can produce an apparent upregulation of the most transcribed genes, thus demonstrating a feedback loop between translation and mRNA degradation [24][25][26]. On the opposite, enhancement of translation can be accompanied by decrease of mRNA stability and consequent reduced mRNA levels [24].…”

Human antigen R as a predictive marker for response to gemcitabine-based chemotherapy in advanced cisplatin-resistant urothelial cancer.

“…Furthermore, in addition to GEM, high HuR expression levels may regulate the response to paclitaxel via regulation of chemoresistance-associated factors including microRNA (31,32). A previous in vitro study demonstrated that cytoplasmic HuR expression was associated with the efficacy of various anticancer agents (33-35); however, it has also been revealed that HuR is able to mediate chemoresistance in numerous types of cancer (36,37). Further studies are required in order to investigate and elucidate the complex mechanisms underlying the interaction between HuR expression levels and the response of patients to chemotherapy.…”