PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

Abstract

Tumour-initiating cells (TICs) are advocated to constitute the sustaining force to maintain and renew fully established malignancy; however, the molecular mechanisms responsible for these properties are elusive. We previously demonstrated that voltage-gated calcium channel a2d1 subunit marks hepatocellular carcinoma (HCC) TICs. Here we confirm directly that a2d1 is a HCC TIC surface marker, and identify let-7c, miR-200b, miR-222 and miR-424 as suppressors of a2d1 þ HCC TICs. Interestingly, all the four miRNAs synergistically target PBX3, which is sufficient and necessary for the acquisition and maintenance of TIC properties. Moreover, PBX3 drives an essential transcriptional programme, activating the expression of genes critical for HCC TIC stemness including CACNA2D1, EpCAM, SOX2 and NOTCH3. In addition, the expression of CACNA2D1 and PBX3 mRNA is predictive of poor prognosis for HCC patients. Collectively, our study identifies an essential signalling pathway that controls the switch of HCC TIC phenotypes.

MicroRNA-33a-3p suppresses cell migration and invasion by directly targeting PBX3 in human hepatocellular carcinoma

“…It was shown that PBX3 gene was at the top of list with the smallest P value among all the predicted miR-33a-3p targets. According to the previous literatures, PBX3 is essential for the acquisition and maintenance of the liver tumor-initiating cells properties, which is generally considered to be closely correlated with tumor migration and metastasis [17, 18]. The computational analysis revealed that miR-33a-3p bound to the 3′-UTR of PBX3 with seed length of 12 and 13 nt.…”

“…Han et al found that PBX3 was able to reverse the suppressive effects of let-7c on colorectal cancer growth and metastasis [17]. Their group also demonstrated that PBX3 is targeted by multiple miRNAs and is essential for tumor-initiating liver cells [18]. Accordingly, the present study demonstrates that PBX3 , as one of the direct targets of miR-33a-3p, is able to override the suppressive effects of miR-33a-3p on HCC growth and metastasis as well.…”

“…However, the underlying mechanisms of PBX3 to influence cancer aggressiveness remains to be investigated. In the literature, PBX3 is sufficient and necessary for the acquisition and maintenance of tumor-initiating cells (TIC) properties [18]. It triggers an essential transcriptional programme by activating critical genes for HCC TIC stemness that including SALL2, SOX2, CACNA2D1, WNT10A, NOTCH3, EpCAM, THY-1 and so on [18].…”

“…In the literature, PBX3 is sufficient and necessary for the acquisition and maintenance of tumor-initiating cells (TIC) properties [18]. It triggers an essential transcriptional programme by activating critical genes for HCC TIC stemness that including SALL2, SOX2, CACNA2D1, WNT10A, NOTCH3, EpCAM, THY-1 and so on [18]. In the present study, we tested one of them, CACNA2D1, a previously experimentally confirmed marker of TIC as a target of PBX3, but our data failed to display reverse regulation of CACNA2D1 by miR-33a-3p.…”

A directly negative interaction of miR-203 and ZEB2 modulates tumor stemness and chemotherapy resistance in nasopharyngeal carcinoma

“…Knocking down ZEB2 significantly suppressed the percentage of SP cells and DDP resistance by reducing the expression of tumor stemness factors including BMI1, SOX2, NANOG, and OCT4. In prvious documents, BMI1 and SOX2 were the key tumor stemness factors [35–39], which had been documented as the direct targets of miR-200 family members. Interestingly, ZEB2 was the directly upstream regulator of miR-200 family members.…”