Alternative splicing variant of RHBDD2 is associated with cell stress response and breast cancer progression

Canzoneri, Romina; Rabassa, Martín Enrique; Gurruchaga, Agustina; Ferretti, Valeria Alejandra; Palma, Sebastián; Isla-Larrain, M.; Croce, María Virginia; Lacunza, Ezequiel; Abba, Martı́n C.

doi:10.3892/or.2018.6489

Cited by 8 publications

(9 citation statements)

References 29 publications

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“…WWOX mRNA was primarily expressed in differentiated cells. These results were consistent with previous studies in rat mammary gland development and human breast cancer cells, indicating that RHBDD2 is highly expressed in proliferating cells (10,11,28). Co-IP suggested that RHBDD2-WWOX protein interaction primarily occured in the membrane fraction of proliferating cells and decreased in differentiated cells.…”

Section: Discussionsupporting

confidence: 92%

RHBDD2‑WWOX protein interaction during proliferative and differentiated stages in normal and breast cancer cells

et al. 2021

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Rhomboid pseudoproteases are catalytically inactive members of the rhomboid superfamily that modulate the traffic, turnover and activity of their target proteins. Rhomboid domain containing 2 (RHBDD2) is a rhomboid family member overexpressed during mammary gland development and advanced stages of breast cancer. Interactome profiling studies have identified RHBDD2 as a novel binding partner of WW domain-containing oxidoreductase (WWOX) protein.The present study characterized the RHBDD2-WWOX interaction in proliferating and differentiated stages of normal mammary and breast cancer cells by co-immunoprecipitation and confocal microscopy. Normal breast and proliferating cancer cells showed significantly increased RHBDD2 mRNA levels compared with their differentiated counterparts. WWOX mRNA was primarily expressed in differentiated cells. WWOX co-precipitated with RHBDD2, indicating that endogenous RHBDD2 and WWOX were physically associated in normal and breast cancer proliferating cells compared with the differentiated stage. Co-localization assays corroborated the co-immunoprecipitation results, demonstrating the RHBDD2-WWOX protein interaction in normal and proliferating breast cancer cells. RHBDD2 harbors a conserved LPPY motif at the C-terminus region that directly interacted with the WW domains of WWOX. Since WWOX serves as an inhibitor of the TGFβ/SMAD3 signaling pathway in breast cells, modulation of SMAD3 target genes was analyzed in proliferating and differentiated mammary cells and in RHBDD2 silencing assays. Increased expression levels of SMAD3-regulated genes were detected in proliferating cells compared with their differentiated counterparts. Follistatin and angiopoietin-like 4 mRNA was significantly downregulated in RHBDD2 transiently silenced cells compared with scrambled control small interfering RNA. Based on these results, WWOX was suggested to be a novel RHBDD2 target protein involved in the modulation of breast epithelial cell proliferation and differentiation.

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Section: Discussionsupporting

confidence: 92%

RHBDD2‑WWOX protein interaction during proliferative and differentiated stages in normal and breast cancer cells

et al. 2021

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“…Members of the rhomboid superfamily are six- or seven-transmembrane proteins, which have been shown to be widely present and may take part in a variety of important biological processes, including cytokine secretion [ 1 – 5 ], protein quality control [ 6 – 9 ], epithelial cell polarity [ 10 ], subcellular transport [ 11 ], and mitochondrial function regulation [ 12 ]. They are also shown to be associated with disease development such as in cancers [ 13 – 17 ] and autoimmune diseases [ 18 – 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…important biological processes, including cytokine secretion [1][2][3][4][5], protein quality control [6][7][8][9], epithelial cell polarity [10], subcellular transport [11], and mitochondrial function regulation [12]. They are also shown to be associated with disease development such as in cancers [13][14][15][16][17] and autoimmune diseases [18][19][20].…”

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confidence: 99%

RHBDF2 gene functions are correlated to facilitated renal clear cell carcinoma progression

et al. 2021

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Background The rhomboids are a family of multi-transmembrane proteins, many of which have been implicated in facilitating tumor progression. Little is yet known, however, about rhomboid-associated biomarkers in cancers. An analysis of such biomarkers could yield important insights into the role of the rhomboids in cancer pathology. Methods In this study, we carried out the univariate Cox regression analysis and compared gene expression patterns of several rhomboid genes in 30 types of cancers by using The Cancer Genome Atlas (TCGA) database and the methods delineated in Gene Expression Profiling Interactive Analysis (GEPIA). We then used datasets GSE47032, GSE126964, GSE68417 and 75 paired pathological specimens to verify the influences of the rhomboid genes in cancer progression. Moreover, we carried out Weighted Gene Correlation Network Analysis (WGCNA) to investigate gene-related functions and we exploited potential correlations between rhomboid genes expression and immune cell infiltration in cancer tissues. Furthermore, we constructed gene-knockdown cancer cell lines to investigate rhomboid gene functions. Results We find that kidney renal clear cell carcinoma (KIRC) disease progression is affected by fluctuations in the expression of a number of the rhomboid family of genes and, more specifically, high levels of RHBDF2 gene expression are a good indicator of poor prognosis of the disease, as patients with high RHBDF2 expression levels exhibit less favorable survival rates compared to those with low RHBDF2 levels. Silencing of the RHBDF2 gene in KIRC cell lines leads to significantly diminished cell proliferation and migration; this is in good agreement with the identification of an enhanced presence of a number of cell growth and migration promoting signaling molecules in KIRC tumors. We found that, although high level of RHBDF2 correlated with increased infiltration of lymphocytes in cancer tissues, artificially overexpressed RHBDF2 led to an inhibition of the activity of the infiltrated immune cells through sustaining PD-L1 protein level. Furthermore, we show that RHBDF2 related cell migration and PD-L1 regulation were potentially mediated by EGFR signaling pathway. Conclusions RHBDF2 gene functions are correlated to facilitated renal clear cell carcinoma progression and may serve as a critical prognostic biomarker for the disease.

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“…Because of the structural variation (AS) in gene transcripts, it is possible that protein translation will be affected, thereby modifying the characteristics of the proteins 27 , 28 . Therefore, it is very important to understand the interaction between DSGs from the perspective of the protein network.…”

Section: Resultsmentioning

confidence: 99%

Profiles of alternative splicing events in the diagnosis and prognosis of Gastric Cancer

Wei¹,

Xie²,

Huang³

et al. 2021

J. Cancer

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Background: Gastric cancer (GC) is a heterogeneous disease, and alternative splicing (AS) is a powerful universal transcriptional regulatory mechanism that contributes to the occurrence and development of cancer. However, the systematic analysis of AS events in GC is lacking; therefore, further studies are needed. Methods: Genome-wide analysis of AS events was performed using RNA-Seq data to evaluate the difference between GC and adjacent tissues at the AS level. Prognostic signatures based on differentially expressed alternative splicing (DEAS) events and a correlation network between DEAS and genes were built. Results: We identified 48,141 AS events, of which 2325 showed differential expression patterns. The parental genes before DEAS events play an essential role in regulating GC-related processes such as ribosome (FDR < 0.0001) and thermogenesis (FDR = 0.0002). There were 76 survival-associated DEAS cases. Stratifying patients according to the percent spliced in index value of six types of splicing patterns formed significant Kaplan-Meier curves in the overall survival analysis. A prognostic feature based on DEAS performed well for stratification in patients with GC. Conclusion: The present study will enrich our understanding regarding the distinction of GC and provide a generous amount of biomarkers and potential targets for the treatment of GC.

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Alternative splicing variant of RHBDD2 is associated with cell stress response and breast cancer progression

Cited by 8 publications

References 29 publications

RHBDD2‑WWOX protein interaction during proliferative and differentiated stages in normal and breast cancer cells

RHBDD2‑WWOX protein interaction during proliferative and differentiated stages in normal and breast cancer cells

RHBDF2 gene functions are correlated to facilitated renal clear cell carcinoma progression

Profiles of alternative splicing events in the diagnosis and prognosis of Gastric Cancer

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