The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone

Fournier, Pierrick G.J.; Juàrez, Patricia; Jiang, Guanglong; Clines, Gregory A.; Niewolna, Maria; Kim, Hun Soo; Walton, Holly W.; Peng, Chunfang; Liu, Yunlong; Mohammad, Khalid S.; Wells, Clark D.; Chirgwin, John M.; Guise, Theresa A.

doi:10.1016/j.ccell.2015.04.009

Cited by 181 publications

(173 citation statements)

References 51 publications

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“…5 Taken together, TMEPAI is suspected as oncogenic protein. In contrast to above results, Fournier et al 17 recently reported that low of TMEPAI correlates with poor metastasis-free survival and TMEPAI knockdown increases prostate cancer metastases in a mouse model. 17 All the opposite results suggested that TMEPAI has an important function in cancer.…”

Section: Discussioncontrasting

confidence: 65%

TMEPAI genome editing in triple negative breast cancer cells

et al. 2017

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ABSTRAK ABSTRACTBackground: Clustered regularly interspaced short palindromic repeats/CRISPR-associated 9 (CRISPR/Cas9) is a powerful genome editing technique. It consists of RNA-guided DNA endonuclease Cas9 and single guide RNA (gRNA). By combining their expressions, high efficiency cleavage of the target gene can be achieved, leading to the formation of DNA double-strand break (DSB) at the genomic locus of interest which will be repaired via NHEJ (non-homologous end joining) or HDR (homology-directed repair) and mediate DNA alteration. We aimed to apply the CRISPR/Cas9 technique to knock-out the transmembrane prostate androgen-induced protein (TMEPAI) gene in the triple negative breast cancer cell line.

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Section: Discussioncontrasting

confidence: 65%

TMEPAI genome editing in triple negative breast cancer cells

et al. 2017

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“…This hypothesis was convinced by overexpression of TMEPAI in MM cells and resultant MM cell apoptosis. Previous studies showed that TMEPAI does not induce apoptosis of prostate cancer cells but inhibits their proliferation (8,25) and prevents their metastasis (10). This finding is contradicted with its role in some solid cancers, such as lung, ovarian and breast cancers (5,6,11).…”

Section: Discussionmentioning

confidence: 95%

“…4A). A previous study found that TMEPAI has three isoforms, of which the cytosolic form TMEPAIc lacks the TM domain and loses its transcriptional activity (10), suggesting the TM domain is critical for TMEPAI activity. To find out whether the TM domain is critical for TMEPAI-mediated c-Maf ubiquitination and stability, we made a series of short truncates of TMEPAI as shown in Fig.…”

Section: The Transmembrane Domain Is Indispensable For Tmepai-mediatementioning

confidence: 98%

“…The specific expression pattern suggests that TMEPAI might function differently upon specific cancer types. For example, TMEPAI displays as a tumor suppressor in prostate cancer progression because silence of TMEPAI leads to accelerated proliferation of prostate cancer cells (8) while expression of TMEPAI inhibits prostate cancer cell growth (9) and prevents its bone metastasis (10). However, TMEPAI acts as an oncogene and promotes proliferation and survival of lung and breast cancers.…”

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confidence: 99%

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The transmembrane protein TMEPAI induces myeloma cell apoptosis by promoting degradation of the c-Maf transcription factor

Liu

et al. 2018

Journal of Biological Chemistry

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Transmembrane prostate androgen-induced protein (TMEPAI, also called prostate transmembrane protein, androgen induced 1 [PMEPA1]), is a type I transmembrane (TM) protein, but its cellular function is largely unknown. Here, studying factors influencing the stability of c-Maf, a critical transcription factor in multiple myeloma (MM), we found that TMEPAI induced c-Maf degradation. We observed that TMEPAI recruited neural precursor cell expressed, developmentally down-regulated 4 (NEDD4), a WW domain-containing ubiquitin ligase, to c-Maf, leading to its degradation through the proteasomal pathway. Further investigation revealed that TMEPAI interacts with NEDD4 via its conserved PY motifs. Alanine substitution or deletion of these motifs abrogated the TMEPAI complex formation with NEDD4, resulting in failed c-Maf degradation. Functionally, TMEPAI suppressed the transcriptional activity of c-Maf. Of note, increased TMEPAI expression was positively associated with the overall survival of MM patients. Moreover, (1). In addition to androgen, TMEPAI expression is also stimulated by some growth factors such as epidermal growth factor (EGF) and transforming growth factor-β (TGF-β) (2). The expression profiling found that TMEPAI is overexpressed in solid cancers including prostate cancer , lung (3,4), breast (3,5) and ovarian cancers (6), and rental cell carcinoma (7), but it is not detectable in liquid cancers such as leukemia and lymphoma samples (7). The specific expression pattern suggests that TMEPAI might function differently upon specific cancer types. For example, TMEPAI displays as a tumor suppressor in prostate cancer progression because silence of TMEPAI leads to accelerated proliferation of prostate cancer cells (8) while expression of TMEPAI inhibits prostate cancer cell growth (9) and prevents its bone metastasis (10). However, TMEPAI acts as an oncogene and promotes proliferation and survival of lung and breast cancers. TMEPAI mediates the degradation of receptor-activated SMAD and activates non-canonical PI3K/AKT signaling transduction thus promoting TGF-β-dependent cell growth and metastasis of triple negative breast cancer (3). In lung cancer cells, TMEPAI not only increases cancer cell proliferation, migration and invasion (11,12) but also enhances tumorigenicity and the epithelial-mesenchymal transition (EMT) of lung cancer cells (4). These actions were associated with TMEPAI-induced TGF-β degradation in lysosomes and TMEPAI-induced reactive oxygen species and insulin receptor substrate-1 (4). In contrast, knockdown of TMEPAI enhances Smad2 phosphorylation and significantly suppressed lung cancer cell proliferation in the presence of TGF-β. All the above results collectively suggest that TMEPAI can promote or suppress cancer cell proliferation and tumor growth depending on the cancer types but the TGF-β signaling pathway is a key factor.Hematological malignancies are a collection of blood cancers including leukemia, lymphoma and multiple myeloma in which TMEPAI is less expressed (7), but the fun...

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“…In prostate cancer, TGFb forms a growth barrier in response to PTEN deletion (43). Paradoxically, it also promotes the expression of prometastatic genes and the development of bone metastases (44). TGFb is also important in the normal prostate, where cellular interactions between luminal epithelial cells and stromal cells determine the amount of active TGFb, in order to maintain tissue homeostasis (45).…”

Section: Discussionmentioning

confidence: 99%

CD73 Expression Is an Independent Prognostic Factor in Prostate Cancer

Leclerc

Charlebois

Chouinard

et al. 2016

Clinical Cancer Research

173

130

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Purpose: CD73 is an adenosine-generating ecto-enzyme that suppresses antitumor immunity in mouse models of cancer, including prostate cancer. Although high levels of CD73 are associated with poor prognosis in various types of cancer, the clinical impact of CD73 in prostate cancer remains unclear.Experimental Design: We evaluated the prognostic value of CD73 protein expression and CD8 þ cell density in 285 cases of prostate cancer on tissue microarray (TMA). Normal adjacent and tumor tissues were evaluated in duplicates.Results: Univariate and multivariate analyses revealed that high levels of CD73 in normal adjacent prostate epithelium were significantly associated with shorter biochemical recurrence (BCR)-free survival. Notably, CD73 expression in normal epithelium conferred a negative prognostic value to prostate-infiltrating CD8 þ cells. Surprisingly, high levels of CD73 in the tumor stroma were associated with longer BCR-free survival in univariate analysis. In vitro studies revealed that adenosine signaling inhibited NF-kB activity in human prostate cancer cells via A2B adenosine receptors. Consistent with these results, CD73 expression in the prostate tumor stroma negatively correlated with p65 expression in the nuclei of prostate tumor cells. Conclusions: Our study revealed that CD73 is an independent prognostic factor in prostate cancer. Our data support a model in which CD73 expression in the prostate epithelium suppresses immunosurveillance by CD8 þ T cells, whereas CD73 expression in the tumor stroma reduces NF-kB signaling in tumor cells via A2B adenosine receptor signaling. CD73 expression, including in normal adjacent prostate epithelium, can thus effectively discriminate between aggressive and indolent forms of prostate cancer.

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The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone

Cited by 181 publications

References 51 publications

TMEPAI genome editing in triple negative breast cancer cells

TMEPAI genome editing in triple negative breast cancer cells

The transmembrane protein TMEPAI induces myeloma cell apoptosis by promoting degradation of the c-Maf transcription factor

CD73 Expression Is an Independent Prognostic Factor in Prostate Cancer

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