Deregulation of SET is Associated with Tumor Progression and Predicts Adverse Outcome in Patients with Early-Stage Colorectal Cancer

Cristóbal, Ion; Torrejón, Blanca; Rubio, Jaime; Santos, Andrea; Pedregal, Manuel; Caramés, Cristina; Zazo, Sandra; Luque, Melani; Sanz-Álvarez, Marta; Madoz‐Gúrpide, Juan; Rojo, Federico; Garcı́a-Foncillas, Jesús

doi:10.3390/jcm8030346

Cited by 21 publications

(16 citation statements)

References 47 publications

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“…We observed that the miR-199b/SET axis plays a key role in determining 5-FU resistance, and both miR-199b and SET predicted the responses to CRT in our LARC cohort [32]. Although SET overexpression has also been described as able to predict worse prognoses in early-stage CRC [33], several differences highlight the prognostic value of miR-199b. This issue is based on the fact that this miR contributes to CRC progression toward the regulation of several other targets besides SET, and that miR-199b was found to be downregulated in around only 50% of cases with metastatic CRC and high SET expression [23].…”

Section: Discussionmentioning

confidence: 71%

MicroRNA-199b Deregulation Shows a Strong SET-Independent Prognostic Value in Early-Stage Colorectal Cancer

Cristóbal

Rubio

Torrejón

et al. 2020

JCM

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The endogenous PP2A inhibitor SET Nuclear Proto-Oncogene (SET) has been reported to play oncogenic roles and determines poor outcomes in colorectal cancer (CRC). Our group previously showed that miR-199b is deregulated in metastatic CRC, and reduced the cell viability and enhanced the sensitivity of CRC cells to standard induction chemotherapy drugs, mainly through direct negative SET regulation. Clinically, miR-199b downregulation was identified as the molecular mechanism responsible for SET overexpression in around half of metastatic CRC patients. However, the potential clinical value of miR-199b in early-stage CRC remains totally unknown. Thus, here we explored the expression levels of this microRNA in a cohort of 171 early-stage CRC patients using real-time polymerase chain reactions. MiR-199b downregulation was found in 21.6% of cases (37 out of 171) and was significantly associated with those patients with a worse Eastern Cooperative Oncology Group (ECOG) status (p = 0.045). Moreover, miR-199b downregulation predicted shorter overall (p < 0.001) and progression-free survival (p = 0.015). As expected, we next immunohistochemically analyzed SET, observing that it was significantly associated with miR-199b in our cohort. However, multivariate analyses showed that miR-199b was an independent biomarker of poor outcomes in early-stage CRC with a predictive value stronger than SET. In conclusion, our results highlight the potential clinical usefulness of miR-199b and suggest that it could represent a novel molecular target in this disease.

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Section: Discussionmentioning

confidence: 71%

MicroRNA-199b Deregulation Shows a Strong SET-Independent Prognostic Value in Early-Stage Colorectal Cancer

Cristóbal

Rubio

Torrejón

et al. 2020

JCM

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“…Moreover, our group recently reported that miR-199b downregulation was significantly associated with SET overexpression in a set of 29 CRC patients without metastatic disease. Notably, seven out of 29 cases had SET overexpressed, and three out of those seven SET-overexpressing cases showed a concomitant miR-199b downregulation, which suggests that this alteration is a contributing mechanism to deregulate SET in early-stage CRC [ 39 ]. We observed here an inverse correlation between miR-199 and SET expression in LARC.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-199b Downregulation Confers Resistance to 5-Fluorouracil Treatment and Predicts Poor Outcome and Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Patients

Cristóbal

Rubio

Santos

et al. 2020

Cancers

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Neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy followed by mesorectal excision is the current standard treatment in locally advanced rectal cancer (LARC) and the lack of complete response represents a major problem that compromises long-term patient survival. However, there is a lack of robust established markers predictive of response to this preoperative treatment available in the clinical routine. The tumor suppressor microRNA (miR)-199b directly targets the PP2A inhibitor SET, which has been involved in 5-FU resistance, and its downregulation has been found to correlate with poor outcome in metastatic colorectal cancer. Here, we studied the functional effects of miR-199b on 5-FU sensitivity after its ectopic modulation, and its expression was quantified by real-time-PCR in a cohort of 110 LARC patients to evaluate its potential clinical significance. Interestingly, our findings demonstrate that miR-199b enhances the sensitivity of colorectal cancer cells to 5-FU in a SET-dependent manner, and that both miR-199b overexpression and SET inhibition are able to overcome resistance to this drug using an acquired 5-FU-resistant model. MiR-199b was found downregulated in 26.4% of cases and was associated with positive lymph node levels after chemoradiotherapy (CRT, p = 0.007) and high pathological stage (p = 0.029). Moreover, miR-199b downregulation determined shorter overall (p = 0.003) and event-free survival (p = 0.005), and was an independent predictor of poor response to preoperative CRT (p = 0.004). In conclusion, our findings highlight the clinical impact of miR-199b downregulation predicting poor outcome and pathological response in LARC, and suggest the miR-199b/SET signaling axis as a novel molecular target to prevent the development of resistance to 5-FU treatment.

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“…Consistent with the tumor suppressor role of PP2A, the PP2A inhibitors, inhibitor-2 of protein phosphatase-2A (SET) and cancerous inhibitor of PP2A (CIP2A), are overexpressed in a variety of cancers [122][123][124][125][126]. These proteins function to prevent PP2A-B subunits from binding the PP2A A-C core complex, decreasing global PP2A activity and contributing to therapeutic resistance [127,128].…”

Section: Indirect Protein Phosphatase 2a (Pp2a) Activationmentioning

confidence: 97%

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Allen-Petersen¹,

Sears²

2019

BioDrugs

131

110

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MYC is a master transcriptional regulator that controls almost all cellular processes. Over the last several decades, researchers have strived to define the context-dependent transcriptional gene programs that are controlled by MYC, as well as the mechanisms that regulate MYC function, in an effort to better understand the contribution of this oncoprotein to cancer progression. There are a wealth of data indicating that deregulation of MYC activity occurs in a large number of cancers and significantly contributes to disease progression, metastatic potential, and therapeutic resistance. Although the therapeutic targeting of MYC in cancer is highly desirable, there remain substantial structural and functional challenges that have impeded direct MYC-targeted drug development and efficacy. While efforts to drug the 'undruggable' may seem futile given these challenges and considering the broad reach of MYC, significant strides have been made to identify points of regulation that can be exploited for therapeutic purposes. These include targeting the deregulation of MYC transcription in cancer through small-molecule inhibitors that induce epigenetic silencing or that regulate the G-quadruplex structures within the MYC promoter. Alternatively, compounds that disrupt the DNA-binding activities of MYC have been the long-standing focus of many research groups, since this method would prevent downstream MYC oncogenic activities regardless of upstream alterations. Finally, proteins involved in the post-translational regulation of MYC have been identified as important surrogate targets to reduce MYC activity downstream of aberrant cell stimulatory signals. Given the complex regulation of the MYC signaling pathway, a combination of these approaches may provide the most durable response, but this has yet to be shown. Here, we provide a comprehensive overview of the different therapeutic strategies being employed to target oncogenic MYC function, with a focus on post-translational mechanisms.

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Deregulation of SET is Associated with Tumor Progression and Predicts Adverse Outcome in Patients with Early-Stage Colorectal Cancer

Cited by 21 publications

References 47 publications

MicroRNA-199b Deregulation Shows a Strong SET-Independent Prognostic Value in Early-Stage Colorectal Cancer

MicroRNA-199b Deregulation Shows a Strong SET-Independent Prognostic Value in Early-Stage Colorectal Cancer

MicroRNA-199b Downregulation Confers Resistance to 5-Fluorouracil Treatment and Predicts Poor Outcome and Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Patients

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

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