RHBDD2: a 5-fluorouracil responsive gene overexpressed in the advanced stages of colorectal cancer

Lacunza, Ezequiel; Canzoneri, Romina; Rabassa, Martín Enrique; Zwenger, Ariel Osvaldo; Segal‐Eiras, Amada; Croce, María Virginia; Abba, Martı́n C.

doi:10.1007/s13277-012-0503-3

Cited by 24 publications

(26 citation statements)

References 17 publications

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“…More recently, we also observed significant RHBDD2 mRNA and protein overexpression in the advanced stages of colorectal cancer (Lacunza et al 2012), suggesting that RHBDD2 up-modulation might be associated with breast and colon cancer malignant progression. We also determined that RHBDD2 protein expression is upregulated in colon cancer cells treated with the chemotherapeutic agent 5-fluourouracil (5FU) (Lacunza et al 2012), which has recently been shown to be an inducer of ER stress in hepatocellular carcinoma cells (Yadunandam et al 2012).…”

Section: Introductionmentioning

confidence: 58%

“…In this sense, we recently demonstrated that the chemotherapy agent 5FU treatment on colorectal cancer cells significantly increases RHBDD2 mRNA and protein expression, compared with the untreated cells, suggesting that RHBDD2 up-modulation might be induced as an adaptive cellular response to the 5FU cytotoxic effects (Lacunza et al 2012). Interestingly, a recent study showed that 5FU promotes ER stress, activating the mitochondrial apoptotic cell death process (Yadunandam et al 2012).…”

Section: Discussionmentioning

confidence: 96%

“…In previous studies, we demonstrated that RHBDD2 is overexpressed at mRNA and protein levels in advanced stages of breast and colorectal carcinomas, suggesting that RHBDD2 up-modulation might be associated with tumor progression (Abba et al 2009: Lacunza et al 2012. In the present study, with the aim of identifying molecular pathways associated to RHBDD2, by the analysis of gene expression microarray data and subsequent experimental approaches by quantitative realtime PCR, we determined that RHBDD2 abrogation in T47D breast cancer cells disrupts the UPR signaling pathway, affecting cellular proliferation and migration in vitro.…”

Section: Discussionmentioning

confidence: 97%

“…In addition, various rhomboid protein family members have been associated with diseases such as neurodegenerative disorders and cancer (Whitworth et al 2008;Zou et al 2009;Abba et al 2009;Blaydon et al 2012;Lacunza et al 2012;Etheridge et al 2013). The specific molecular function of several of the proteolytically inactive rhomboids in particular remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Identification of signaling pathways modulated by RHBDD2 in breast cancer cells: a link to the unfolded protein response

Lacunza

Rabassa

Canzoneri

et al. 2014

Cell Stress and Chaperones

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Rhomboid domain containing 2 (RHBDD2) was previously observed overexpressed and amplified in breast cancer samples. In order to identify biological pathways modulated by RHBDD2, gene expression profiles of RHBDD2 silenced breast cancer cells were analyzed using whole genome human microarray. Among the statistically significant overrepresented biological processes, we found protein metabolism-with the associated ontological terms folding , ubiquitination , and proteosomal degradation-cell death, cell cycle, and oxidative phosphorylation. In addition, we performed an in silico analysis searching for RHBDD2 co-expressed genes in several human tissues. Interestingly, the functional analysis of these genes showed similar results to those obtained with the microarray data, with negative regulation of protein metabolism and oxidative phosphorylation as the most enriched gene ontology terms. These data led us to hypothesize that RHBDD2 might be involved in endoplasmic reticulum (ER) stress response. Thus, we specifically analyzed the unfolding protein response (UPR) of the ER stress process. We used a lentivirus-based approach for stable silencing of RHBDD2 mRNA in the T47D breast cancer cell line, and we examined the transcriptional consequences on UPR genes as well as the phenotypic effects on migration and proliferation processes. By employing dithiothreitol as an UPR inducer, we observed that cells with silenced RHBDD2 showed increased expression of ATF6, IRE1, PERK, CRT, BiP, ATF4, and CHOP (p <0.01). We also observed that RHBDD2 silencing inhibited colony formation and decreased cell migration. Based on these studies, we hypothesize that RHBDD2 overexpression in breast cancer could represent an adaptive phenotype to the stressful tumor microenvironment by modulating the ER stress response.

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Section: Introductionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Identification of signaling pathways modulated by RHBDD2 in breast cancer cells: a link to the unfolded protein response

Lacunza

Rabassa

Canzoneri

et al. 2014

Cell Stress and Chaperones

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“…The authors indicate that expression of RHBDD2 significantly increases in advanced stages of colorectal cancer. Also, they found a significant increase of RHBDD2 mRNA and protein after treatment with the chemotherapy agent 5-fluorouracil (41).…”

Section: Discussionmentioning

confidence: 95%

Dynamics of the Rhomboid-like Protein RHBDD2 Expression in Mouse Retina and Involvement of Its Human Ortholog in Retinitis Pigmentosa

Ahmedli¹,

Gribanova²,

Njoku³

et al. 2013

Journal of Biological Chemistry

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Background: RHBDD2 is distantly related to rhomboids, membrane-bound proteases. Results: In retina, RHBDD2 exists as a monomer in all cells throughout life and a homotrimer only in cone outer segments; a mutation in RHBDD2 possibly leads to retinitis pigmentosa. Conclusion: RHBDD2 plays important roles in development and normal retinal function. Significance: This is the first characterization of RHBDD2 and its association with retinal disease.

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Rhomboid family gene expression profiling in breast normal tissue and tumor samples

et al. 2013

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Rhomboid is an evolutionary conserved and functionally diversified group of proteins composed of proteolytically active and inactive members that are involved in the modulation of multiple biological processes such as epidermal growth factor receptor signaling pathway, endoplasmic reticulum-associated degradation, cell death, and proliferation. Recently, several human rhomboid genes have been associated with the development of chronic myeloid leukemia and pituitary, colorectal, ovarian, and breast cancers. In this study, we evaluated the mRNA and protein expression profiles of rhomboid genes in cancer cell lines and breast tissue/tumor samples. In silico analysis of publicly available gene expression datasets showed that different rhomboid genes are specifically expressed according to the breast cancer intrinsic subtypes. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis showed a significant RHBDD2 mRNA overexpression in advanced breast cancer compared with normal tissue samples (p = 0.012). In addition, we found that RHBDL2 and PARL mRNA expression was associated with a low/intermediate histologic tumor grade (p = 0.024 and p = 0.015, respectively). Immunohistochemistry analysis showed a significant increase of RHBDD2 protein expression in association with breast cancer samples negative for progesterone receptor (p = 0.015). Moreover, protein expression analysis corroborated the quantitative RT-PCR results, indicating that breast primary tumors belonging to patients with a more disseminated disease expressed significantly increased levels of RHBDD2 protein compared with less disseminated tumors (p = 0.01).

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RHBDD2: a 5-fluorouracil responsive gene overexpressed in the advanced stages of colorectal cancer

Cited by 24 publications

References 17 publications

Identification of signaling pathways modulated by RHBDD2 in breast cancer cells: a link to the unfolded protein response

Identification of signaling pathways modulated by RHBDD2 in breast cancer cells: a link to the unfolded protein response

Dynamics of the Rhomboid-like Protein RHBDD2 Expression in Mouse Retina and Involvement of Its Human Ortholog in Retinitis Pigmentosa

Rhomboid family gene expression profiling in breast normal tissue and tumor samples

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