Pseudogene PTENP1 functions as a competing endogenous RNA (ceRNA) to regulate PTEN expression by sponging miR-499-5p

Wang, Lei; Zhang, Ning; Wang, Zun; Ai, Dongmei; Cao, Zhenyu; Pan, Huaping

doi:10.1134/s0006297916070105

Cited by 21 publications

(17 citation statements)

References 18 publications

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“…Additionally, our data manifested that MT1H slightly affected the activation of RhoC-based signaling pathway and Cd-induced cell death through miR-214, suggesting a little contribution of MT1H to the activation of MT1DP/RhoC-CCN1/2-AKT pathway and resultant cell death outcome via miR-214. Although such a mutual ceRNA mechanism between protein-coding genes and their pseudogenes has not been extensively investigated, increasing evidence supports our finding on the reciprocal ceRNA mechanism between pseudogenes and their parental genes through competing for common miRNAs 43 , 73 such as cytochrome P450 family 2 subfamily A member 6 (CYP2A6) and its pseudogene CYP2A7 and phosphatase and tensin homolog deleted on chromosome ten (PTEN) and its pseudogene PTENP1 74 , 75 .…”

Section: Discussionsupporting

confidence: 83%

Long non-coding RNA MT1DP shunts the cellular defense to cytotoxicity through crosstalk with MT1H and RhoC in cadmium stress

Gao

Chen

et al. 2018

Cell Discov

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Metallothioneins (MTs) are known to protect cells against oxidative stress, especially providing protection against cadmium (Cd) toxicity in hepatocytes. There are various gene variants and pseudogenes for MTs; however, there is little understanding on the functions of those non-coding MT members that are known to be expressed as long non-coding RNAs (lncRNAs) nowadays. Different from most protein-coding MT members, MT1DP was here found that remarkably induced to provoke cytotoxicity in hepatocytes in response to Cd treatment. MT1DP exerted such a pro-apoptotic function in Cd-treated hepatocytes through interacting with two partners: RhoC and MT1H. On one hand, MT1DP interacted with RhoC protein to increase the latter’s stability by preventing lysosome-dependent protein degradation. Therefore, upon Cd stress, MT1DP/RhoC complex was quickly reinforced to activate RhoC-CCN1/2-AKT signaling and potentiate Ca2+ influx, leading to enhanced Cd uptake and elevated Cd toxicity. On the other hand, MT1H, a protein-coding member of the MT family with little known function, was found to quickly respond to Cd exposure along with MT1DP. Mechanistically, MT1H and MT1DP were uncovered to mutually protect each other through a reciprocal ceRNA mechanism, building up a positive feedback loop to enforce MT1DP-conducted signaling upon Cd exposure. Moreover, MT1DP was found to contribute much more to the activation of RhoC-CCN1/2-AKT signaling than MT1H. Considered together, we here unveiled a mystery whether a pseudogene within the MT family, MT1DP, has actual biological functions in regulating Cd-induced cellular defense. Our findings unearthed an important role of pseudogene MT1DP in calibrating the cellular machinery to switch the cellular defense to cytotoxicity through crosslinking an interplay between its two partners, namely MT1H and RhoC, under cadmium stress.

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Section: Discussionsupporting

confidence: 83%

Long non-coding RNA MT1DP shunts the cellular defense to cytotoxicity through crosstalk with MT1H and RhoC in cadmium stress

Gao

Chen

et al. 2018

Cell Discov

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“…In the present study, we found that the overexpression of lentiviral‐mediated PTENP1 3′UTR significantly inhibited the proliferation of Eca109 and TE‐1 cells. It is known that PTENP1 expression could regulate the expression of PTEN . However, we only observed elevated expression of PTEN in Eca109 whereas no significant alteration was found in TE‐1 cell line.…”

Section: Discussioncontrasting

confidence: 68%

“…It is known that PTENP1 expression could regulate the expression of PTEN. 11,13,15,36 However, we only observed elevated expression of PTEN in Eca109 whereas no significant alteration was found in TE-1 cell line. This may be explained by the variation of the PTENP1 abundance and subcellular localization in different cell lines, which remains to be further validated.…”

Section: Discussioncontrasting

confidence: 61%

PTENP1 inhibits the growth of esophageal squamous cell carcinoma by regulating SOCS6 expression and correlates with disease prognosis

Gong

Zheng

Huang

et al. 2017

Molecular Carcinogenesis

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PTEN pseudogene (PTENP1) has a tumor suppressive role in multiple cancers. However, its involvement in esophageal squamous cell carcinoma (ESCC) remains largely unknown. In this study, we set out to identify the role of PTENP1 in the development of ESCC. Gene Expression Omnibus database was employed to investigate the expression of PTENP1 in ESCC. sRNA target Database (StarBase v2.0) was used to query the downstream of PTENP1. Next, both in vitro and in vivo experiments were employed to explore the function. Cell proliferation was evaluated by CCK‐8, soft agar, and colony formation assays. Expression of relative genes was assessed by quantitative real‐time PCR (qRT‐PCR) and Western blotting. 3′UTR luciferase assay was used to confirm the miRNA binding. The clinical significance of PTENP1 was further validated by immunohistochemistry (IHC) and correlation with clinicopathological indicators in additional samples (n = 93). We found expression of PTENP1 in ESCC was lower than that in the corresponding adjacent normal tissues (n = 17). Overexpression of PTENP1 in Eca109 and TE‐1 cells resulted in inhibited proliferation and altered expression of SOCS6‐p‐STAT3‐HIF‐1α pathway both in vitro and in vivo. Subsequent IHC reported a similar trend in human ESCC samples. 3′UTR luciferase assay demonstrated that PTENP1 3′UTR decoyed miR‐17‐5p from binding to SOCS6. Moreover, PTENP1 expression was correlated with clinicopathological indicators to varying degrees, including histological grade, TNM stage, infiltration depth, lymph node metastasis, and overall survival. Taken together, these results suggested an anti‐oncogenic role of PTENP1. Meanwhile, PTENP1 may also serve as a candidate of prognostic indicator for ESCC patients.

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“…Studies have found PTENP1 to be lost or downregulated in various cancers [3, 5, 6, 8, 10, 11]. In ordert to evaluate PTENP1 status in GC, we determined the levels PTENP1 transcripts by qRT-PCR in 36 GC biopsies and their paired adjacent normal tissues from the same patients.…”

Section: Resultsmentioning

confidence: 99%

Long non-coding RNA PTENP1 functions as a ceRNA to modulate PTEN level by decoying miR-106b and miR-93 in gastric cancer

et al. 2017

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Recent studies have shown that competing endogenous RNAs (ceRNAs) play an important role in the regulation of gene expression, and participate in a wide range of biological processes, including carcinogenesis. Long non-coding RNA PTENP1, the pseudogene of PTEN tumor suppressor, has been reported to exert its tumor suppressive function via modulation of PTEN expression in many malignancies. However, whether a PTENP1∼miRNA∼PTEN ceRNA network exists and how it functions in gastric cancer (GC) remains elusive. In order to identify and characterize the PTENP1∼miRNA∼PTEN ceRNA network in GC, we first determined PTENP1 levels in clinical GC samples and found that PTENP1 and PTEN were concurrently downregulated in these samples. We further demonstrated that PTENP1 could act as a ceRNA to sponge miR-106b and miR-93 from targeting PTEN for downregulation using a novel ceRNA in vitro gradient assay. Thus, we revealed a tumor suppressive role of PTENP1 as ceRNA in GC and pinpointed the specific miRNAs decoyed by PTENP1, highlighting the emerging roles of ceRNAs in the biological regulation of GC cells and their possible clinical significance.

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Pseudogene PTENP1 functions as a competing endogenous RNA (ceRNA) to regulate PTEN expression by sponging miR-499-5p

Cited by 21 publications

References 18 publications

Long non-coding RNA MT1DP shunts the cellular defense to cytotoxicity through crosstalk with MT1H and RhoC in cadmium stress

Long non-coding RNA MT1DP shunts the cellular defense to cytotoxicity through crosstalk with MT1H and RhoC in cadmium stress

PTENP1 inhibits the growth of esophageal squamous cell carcinoma by regulating SOCS6 expression and correlates with disease prognosis

Long non-coding RNA PTENP1 functions as a ceRNA to modulate PTEN level by decoying miR-106b and miR-93 in gastric cancer

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