Preclinical studies using miR‐32‐5p to suppress clear cell renal cell carcinoma metastasis <i>via</i> altering the miR‐32‐5p/TR4/HGF/Met signaling

Wang, Mingchao; Sun, Yin; Xu, Junjie; Lu, Jinmei; Wang, Kefeng; Yang, Dian; Yang, Guosheng; Li, Gonghui; Chang, Chawnshang

doi:10.1002/ijc.31289

Cited by 40 publications

(54 citation statements)

References 43 publications

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“…Targeting TR4/lncTASR/AXL signaling with small molecules including TR4-shRNA, tretinoin, or metformin all led to increase sunitinib sensitivity to better suppress the RCC progression To link the above findings to the future potential clinical application, we were interested to find if any small molecules can be used as possible therapeutic interventions to target this newly identified TR4/lncTASR/AXL signaling. Among several likely candidates, including TR4-siRNAs [25,26], miRNAs [22], TR4 potential antagonists/agonists including tretinoin (Hu et al unpublished data), and metformin [27] that can suppress the TR4 function, we found that adding TR4-shRNA (See Fig. 1f, g), metformin or tretinoin (up to 10 μM), could also result in increasing the sunitinib sensitivity to better suppress the RCC OSRC-2 cell growth (Fig.…”

Section: Human Clinical Data Support the Tr4/lnctasr/axl Axis In The mentioning

confidence: 82%

“…As recent studies indicated that TR4 could also impact RCC progression [21,22], we were interested to see if hypoxia may function via altering TR4 to influence the sunitinib sensitivity. The results revealed that hypoxia could significantly increase TR4 expression in both RCC OSRC-2 and SW839 cells (Fig.…”

Section: Hypoxia Treatment Can Increase Rcc Resistance To Sunitinib Vmentioning

confidence: 99%

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Targeting the TR4 nuclear receptor-mediated lncTASR/AXL signaling with tretinoin increases the sunitinib sensitivity to better suppress the RCC progression

Shi

Sun

et al. 2019

Oncogene

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Renal cell carcinoma (RCC) is one of the most lethal urological tumors. Using sunitinib to improve the survival has become the first-line therapy for metastatic RCC patients. However, the occurrence of sunitinib resistance in the clinical application has curtailed its efficacy. Here we found TR4 nuclear receptor might alter the sunitinib resistance to RCC via altering the TR4/lncTASR/AXL signaling. Mechanism dissection revealed that TR4 could modulate lncTASR (ENST00000600671.1) expression via transcriptional regulation, which might then increase AXL protein expression via enhancing the stability of AXL mRNA to increase the sunitinib resistance in RCC. Human clinical surveys also linked the expression of TR4, lncTASR, and AXL to the RCC survival, and results from multiple RCC cell lines revealed that targeting this newly identified TR4-mediated signaling with small molecules, including tretinoin, metformin, or TR4-shRNAs, all led to increase the sunitinib sensitivity to better suppress the RCC progression, and our preclinical study using the in vivo mouse model further proved tretinoin had a better synergistic effect to increase sunitinib sensitivity to suppress RCC progression. Future successful clinical trials may help in the development of a novel therapy to better suppress the RCC progression.

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Section: Human Clinical Data Support the Tr4/lnctasr/axl Axis In The mentioning

confidence: 82%

Section: Hypoxia Treatment Can Increase Rcc Resistance To Sunitinib Vmentioning

confidence: 99%

Targeting the TR4 nuclear receptor-mediated lncTASR/AXL signaling with tretinoin increases the sunitinib sensitivity to better suppress the RCC progression

Shi

Sun

et al. 2019

Oncogene

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“…The tumor promoting role of TR4 has been documented in various cancers [9][10][11][12][13], promoting scientists to identify TR4 inhibitor for better treatment of cancers. Therefore, it is of importance and interest to develop small molecules which can speci cally inhibit TR4 activity.…”

Section: Discussionmentioning

confidence: 99%

“…As a transcription factor, activated TR4 is translocated to the nucleus where it binds its recognized DNA element and regulates a bundle of genes. Now increasing evidence suggest that TR4 may also contribute to cancer development [9][10][11][12][13]. For instance, TR4 played a tumor promoting role in RCC by promoting vasculogenic mimicry formation and tumor metastasis [9].…”

Section: Introductionmentioning

confidence: 99%

Testicular Orphan Receptor 4 (TR4) Promotes Papillary Thyroid Cancer Invasion via Activating Circ-FNLA/miR-149-5p/MMP9 Signaling

Ouyang

Feng

Yao

et al. 2020

Preprint

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Background: The incidence and mortality of papillary thyroid cancer (PTC) have steadily increased. Although conventional therapies are very effective towards differentiated PTC patients, very limited therapeutic options are applicable to those patients with distant metastases. Therefore, better understanding of the molecular biology of metastatic PTC helps identify novel targets and facilitates the development of new therapies.Methods: Western blot assay was used to check relative gene protein expression. Transwell invasion assay was used to check the invasion capacity of the PTC cells. Wound healing assay was conducted to check the migration capacity of the PTC cells. qRT-PCR assay was used to check relative RNA expression of the cells. IHC assay was used to check TR4 and MMP9 expression in clinical samples or mouse tumor samples. Results: In this study, we first found that testicular orphan receptor 4 (TR4) was significantly increased in PTC tumors spreading to lymph node compared to the paired primary tumors. Experimental evidence suggested that TR4 drove PTC progression via promoting its cell invasion and cell migration. Mechanistically, TR4 transcriptionally regulated the expression level of circ-FLNA, which competed with MMP9 for miR-149-5p binding and led to increased protein level of MMP9. Interruption assays with various gene manipulations verified that TR4/circ-FLNA/miR-149-5p/MMP9 signaling axis played central role in cell invasion and cell migration of PTC cells. Moreover, xenografted mouse model also confirmed that TR4/circ-FLNA signal promoted PTC tumor growth.Conclusions: Overall, our study pinpoints the oncogenic role of TR4 in PTC development and targeting TR4/circ-FLNA/miR-149-5p/MMP9 signaling may be an alternative option for metastatic PTC patients.

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“…The dysregulation of miRs is observed in the majority of types of cancer, including RCC (14). In previous studies, numerous miRs have been demonstrated to be involved in RCC, including miR-720 (15), miR-203 (16), miR-204-3p (17) and miR-32-5p (18). miR-222 is…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‑222‑3p promotes tumor cell migration and invasion and inhibits apoptosis, and is correlated with�an�unfavorable prognosis of patients with renal cell carcinoma

Zhao

Quan

et al. 2018

Int J Mol Med

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The aim of the present study was to investigate the role of microRNA (miR)-222-3p in renal cell carcinoma (Rcc). The expression level of miR-222-3p was detected in Rcc tissues and cell lines (AcHN, 786-O, caki-1 and 769-P) and was identified to be significantly upregulated compared with the level in adjacent normal renal tissues and HK-2 cells. Further in vitro experiments demonstrated that the over expression of miR-222-3p promoted the migration and invasion, and attenuated the apoptosis of 786-O cells, whereas the knockdown of miR-222-3p suppressed the migration and invasion and induced the apoptosis of 786-O cells. Similar results were observed in the ACHN cell line in terms of migration, invasion and apoptosis. Furthermore, the expression level of miR-222-3p was measured in 42 RCC formaldehyde-fixed paraffin-embedded samples, and the association between the expression of miR-222-3p and the pathological characteristics and overall survival rate of patients with Rcc was analyzed. The results demonstrated that patients with a higher expression of miR-222-3p had a significantly lower overall survival rate, compared with those with a lower expression of miR-222-3p [hazard ratio (HR)=5.120; P=0.036]. Multivariate analysis identified that patients with a higher expression of miR-222-3p retained the statistically significant decrease in overall survival rate compared with patients with a lower expression of miR-222-3p (HR=5.636; P=0.030). Furthermore, Kaplan-Meier survival curves indicated that patients with higher miR-222-3p had significantly lower overall survival rates compared with patients with lower miR-222-3p (P=0.020). Taken together, these results suggested that miR-222-3p serves as an onco-miR in RCC and may be a potential prognostic biomarker and therapeutic target in patients with RCC.

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Preclinical studies using miR‐32‐5p to suppress clear cell renal cell carcinoma metastasis via altering the miR‐32‐5p/TR4/HGF/Met signaling

Cited by 40 publications

References 43 publications

Targeting the TR4 nuclear receptor-mediated lncTASR/AXL signaling with tretinoin increases the sunitinib sensitivity to better suppress the RCC progression

Targeting the TR4 nuclear receptor-mediated lncTASR/AXL signaling with tretinoin increases the sunitinib sensitivity to better suppress the RCC progression

Testicular Orphan Receptor 4 (TR4) Promotes Papillary Thyroid Cancer Invasion via Activating Circ-FNLA/miR-149-5p/MMP9 Signaling

MicroRNA‑222‑3p promotes tumor cell migration and invasion and inhibits apoptosis, and is correlated with�an�unfavorable prognosis of patients with renal cell carcinoma

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