miRNA profiles in livers with different mass deficits after partial hepatectomy and miR-106b~25 cluster accelerating hepatocyte proliferation in rats

Xu, Xiao; Liu, Zhikun; Wang, Jianguo; Ling, Qi; Xie, Haiyang; Guo, Huimin; Wei, Xuyong; Zhou, Lin; Zheng, Shusen

doi:10.1038/srep31267

Cited by 16 publications

(12 citation statements)

References 34 publications

(37 reference statements)

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“…Indeed, other studies have reported a tumor suppressive role for members of the miR-106b-25 cluster ( 24 , 33 – 35 ), but most of these studies have examined the role of only a single miRNA within the cluster. Our findings are in line with many other published studies that demonstrate a tumor promotional role for the miR-106b-25 cluster as a whole, as it has been shown to increase proliferation and invasion in hepatocellular ( 36 , 37 ), lung( 17 ), endometrial( 38 ), esophageal( 39 ), and gastric cancers( 18 ), and to increase tumor progression in prostate cancer( 19 ). Our results further solidify an oncogenic role for the miR-106b-25 miRNA cluster in breast cancer, particularly as the cluster is co-expressed behind a single promoter for the MCM7 gene and its effects are thus likely mediated by all three members in coordination.…”

Section: Discussionsupporting

confidence: 93%

The miR-106b-25 cluster mediates breast tumor initiation through activation of NOTCH1 via direct repression of NEDD4L

et al. 2018

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Tumor initiating cells (TIC) represent a subset of tumor cells with increased self-renewal capability. TICs display resistance to frontline cancer treatment and retain the ability to repopulate a tumor after therapy, leading to cancer relapse. NOTCH signaling has been identified as an important driver of the TIC population, yet mechanisms governing regulation of this pathway in cancer remain to be fully elucidated. Here, we identify a novel mechanism of NOTCH regulation and TIC induction in breast cancer, via the miR-106b-25 miRNA cluster. We show that the miR-106b-25 cluster upregulates NOTCH1 in multiple breast cancer cell lines, representing both estrogen receptor (ER+) and triple negative breast cancer (TNBC), through direct repression of the E3 ubiquitin ligase, NEDD4L. We further show that upregulation of NOTCH1 is necessary for TIC induction downstream of miR-106b-25 in both ER+ and TNBC breast cancer cells, and that re-expression of NEDD4L is sufficient to reverse miR106b-25-mediated NOTCH1 upregulation and TIC induction. Importantly, we demonstrate a significant positive correlation between miR-106b-25 and NOTCH1 protein, yet a significant inverse correlation between miR-106b-25 and NEDD4L mRNA in human breast cancer, suggesting a critical role for the miR106b-25/NEDD4L/NOTCH1 axis in the disease. Further, we show for the first time that NEDD4L expression alone is significantly associated with a better relapse free prognosis for breast cancer patients. These data expand our knowledge of the mechanisms underlying NOTCH activation and TIC induction in breast cancer, and may provide new avenues for the development of therapies targeting this resistant subset of tumor cells.

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Section: Discussionsupporting

confidence: 93%

The miR-106b-25 cluster mediates breast tumor initiation through activation of NOTCH1 via direct repression of NEDD4L

et al. 2018

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“…This experiment was repeated three times. For the detailed methods, please refer to the previous publication [ 34 ].…”

Section: Methodsmentioning

confidence: 99%

MCM family in HCC: MCM6 indicates adverse tumor features and poor outcomes and promotes S/G2 cell cycle progression

Li²,

et al. 2018

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BackgroundMinichromosome Maintenance family (MCMs), as replication licensing factors, is involved in the pathogenesis of tumors. Here, we investigated the expression of MCMs and their values in hepatocellular carcinoma (HCC).MethodsMCMs were analyzed in 105 samples including normal livers (n = 15), cirrhotic livers (n = 40), HCC (n = 50) using quantitative polymerase chain reaction (qPCR) (Cohort 1). Significantly up-regulated MCMs were verified in 102 HCC and matched peritumoral livers using PCR (Cohort 2), and the correlations with clinical features and outcomes were determined. In addition, the focused MCMs were analyzed in parallel immunohistochemistry of 345 samples on spectrum of hepatocarcinogenesis (Cohort 3) and queried for the potential specific role in cell cycle.ResultsMCM2–7, MCM8 and MCM10 was significantly up-regulated in HCC in Cohort 1. In Cohort 2, overexpression of MCM2–7, MCM8 and MCM10 was verified and significantly correlated with each other. Elevated MCM2, MCM6 and MCM7 were associated with adverse tumor features and poorer outcomes. In Cohort 3, MCM6 exhibited superior HCC diagnostic performance compared with MCM2 and MCM7 (AUC: 0.896 vs. 0.675 and 0.771, P < 0.01). Additionally, MCM6 other than MCM2 and MCM7 independently predicted poorer survival in 175 HCC patients. Furthermore, knockdown of MCM6 caused a delay in S/G2-phase progression as evidenced by down-regulation of CDK2, CDK4, CyclinA, CyclinB1, CyclinD1, and CyclinE in HCC cells.ConclusionsWe analyze MCMs mRNA and protein levels in tissue samples during hepatocarcinogenesis. MCM6 is identified as a driver of S/G2 cell cycle progression and a potential diagnostic and prognostic marker in HCC.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4056-8) contains supplementary material, which is available to authorized users.

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“…The experiment was performed three times. Further detailed methods are described elsewhere . Cultured cells were collected in RIPA lysis buffer (50 mM Tris‐HCl, 150 mM NaCl, 1% Triton X‐100, 1% sodium deoxycholate, 0.1% SDS, 1 mM PMSF) with 10 mL/mL protease inhibitor cocktail (Sigma, St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

Metallothionein 1 family profiling identifies MT1X as a tumor suppressor involved in the progression and metastastatic capacity of hepatocellular carcinoma

Liu

Ye²,

Wu³

et al. 2018

Molecular Carcinogenesis

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Metallothionein 1 (MT1s) is a family of cysteine-rich proteins with diverse functions such as metal homeostasis, oxidative stress, and carcinogenesis. However, its involvement in hepatocellular carcinoma (HCC) remains not fully understood. We aimed to explore the contribution of the individual member of MT1s to HCC. Its member mRNA levels were determined in cohort 1 of normal (n = 30), cirrhotic (n = 30), peritumoral (n = 135), and HCC (n = 135). In cohort 1, seven of eight members were down-regulated during the transition from normal liver to HCC, and only MT1G and MT1X were correlated with tumor features and outcomes. The MT1X was selected to be further stained in cohort 2 consisting of a series of liver nodules (15 normal livers, 33 cirrhotic livers, 12 dysplastic nodules, 31 HCC, and 9 HCC metastasis), and in cohort 3 (HCC, n = 85). In cohort 2, MT1X immunoreactivity was reduced in HCC and lost in metastatic HCC and showed good diagnostic performance for HCC (AUC = 0.754, 95%IC = 0.659-0.849). In cohort 3, MT1X expression in peritumoral tissues was independent predictor for HCC (recurrence free survival: HR = 0.34, 95%CI = 0.17-0.66; overall survival: HR = 0.32, 95%CI = 0.16-0.60). Moreover, we found that ectopic overexpression of MT1X delayed G1/S progression of cell cycle and promoted apoptosis in HCC cells in vitro, and suppressed tumor growth and lung metastasis in nude mice in vivo. We further demonstrated that MT1X induces cell cycle arrest and apoptosis by inactivating NF-κB signaling in HCC. In conclusion, MT1X may serve as a candidate of prognostic indicator and inhibits the progression and metastasis of HCC.

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miRNA profiles in livers with different mass deficits after partial hepatectomy and miR-106b~25 cluster accelerating hepatocyte proliferation in rats

Cited by 16 publications

References 34 publications

The miR-106b-25 cluster mediates breast tumor initiation through activation of NOTCH1 via direct repression of NEDD4L

The miR-106b-25 cluster mediates breast tumor initiation through activation of NOTCH1 via direct repression of NEDD4L

MCM family in HCC: MCM6 indicates adverse tumor features and poor outcomes and promotes S/G2 cell cycle progression

Metallothionein 1 family profiling identifies MT1X as a tumor suppressor involved in the progression and metastastatic capacity of hepatocellular carcinoma

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