RHBDD2 overexpression promotes a chemoresistant and invasive phenotype to rectal cancer tumors via modulating UPR and focal adhesion genes

Palma, Sebastián; Raffa, C.I.; Garcia-Fabiani, María Belén; Ferretti, Valeria Alejandra; Zwenger, Ariel Osvaldo; Verdera, P.V. Perez; Llontop, Alejandra; Bilbao, Erica Rojas; Cuartero, V.; Abba, Martı́n C.; Lacunza, Ezequiel

doi:10.1016/j.bbadis.2020.165810

Cited by 7 publications

(11 citation statements)

References 63 publications

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“…For example, Tan et al ( 14 ) noted that increasing the expression of DDIT3 enhanced the sensitivity of lung cancer cells to cisplatin. Another study reported that decreased expression of DDIT3 was an important factor underlying the 5-FU resistance of rectal cancer resulting from the high expression of rhomboid domain containing 2 ( 32 ). These reports are consistent with the findings of the present study; apoptosis experiments showed that NDRG4 overexpression enhanced the 5-FU-induced apoptosis of CRC cells, which was significantly weakened by DDIT3-knockdown in NDRG4-overexpressing SW480 cells, indicating the importance of DDIT3 in the apoptosis pathway.…”

Section: Discussionmentioning

confidence: 99%

NDRG4 sensitizes CRC cells to 5‑FU by upregulating DDIT3 expression

Shen

et al. 2021

Oncol Lett

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The incidence of colorectal cancer (CRC) has remained high in recent years, and 5-fluorouracil (5-FU) is a vital chemotherapeutic agent for its treatment. Our previous study reported that N-myc downstream-regulated gene 4 (NDRG4) plays a tumor-suppressive role in CRC, but the mechanisms associated with NDRG4 and 5-FU chemosensitivity remain unclear. The results of the present study demonstrate that NDRG4 sensitized CRC cells to 5-FU by upregulating DNA damage inducible transcript 3 (DDIT3). NDRG4 inhibited the proliferation of CRC cells and the activation of PI3K/AKT and ERK signaling. Furthermore, NDRG4 promoted CRC cell apoptosis induced by 5-FU. Mechanistic analyses revealed that NDRG4 upregulated DDIT3 expression, and that the proapoptotic effect of NDRG4 under 5-FU treatment conditions was dependent on DDIT3. These findings support the biological value of the association between NDRG4, DDIT3 and 5-FU chemosensitivity in CRC, and may advance the clinical treatment of CRC in the future.

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Section: Discussionmentioning

confidence: 99%

NDRG4 sensitizes CRC cells to 5‑FU by upregulating DDIT3 expression

Shen

et al. 2021

Oncol Lett

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“…Adhesion is a critical step in tumor cell metastasis . In particular, heterogeneous adhesion between tumor cells and vascular endothelial cells plays a crucial role.…”

Section: Resultsmentioning

confidence: 99%

Hyaluronic Acid-Modified Nanoparticles Self-Assembled from Linoleic Acid-Conjugated Chitosan for the Codelivery of miR34a and Doxorubicin in Resistant Breast Cancer

Yang

Shang

et al. 2021

Mol. Pharmaceutics

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In this study, a chitosan-based, self-assembled nanosystem that codelivered microRNA34a (miR34a) and doxorubicin (Dox) with hyaluronic acid (HA) modification (named CCmDH NPs) was developed to reverse the resistance of breast cancer (BCa) cells to Dox. The CCmDH NPs had a diameter of 180 ± 8.3 nm and a ζ potential of 16.5 mV with a slow-release effect for 96 h. The codelivery system could protect miR34a from nuclease and serum degradation and transport miR34a and Dox into drug-resistant MCF-7/A cells. In addition, the CCmDH NPs could inhibit proliferation and promote apoptosis by regulating the protein expression of B-cell lymphoma-2 (Bcl-2) and poly(ADP-ribose) polymerase (PARP) and inhibit invasion, metastasis, and adhesion by regulating E-cadherin, N-cadherin, MMP2, CD44, and Snail molecules. The CCmDH NPs induced a 73.7% tumor reduction in xenograft tumor growth in nude mice in vivo. This study provides evidence for the anticancer activity of CCmDH NPs carrying Dox and miR34a in BCa, especially metastatic Dox-resistant BCa models.

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“…RHBDD2 is a member of the rhomboid family of membrane-bound proteases and is known to be overexpressed in the advanced stages of breast cancers and colorectal cancers (Abba et al, 2009) (Lacunza et al, 2012) (Palma et al, 2020). RHBDD2 is also reported that its overexpression promotes chemoresistance and invasive phenotypes of rectal cancer (Palma et al, 2020). However, these previous studies focused on the expression of RHBDD2 in the tumor cells themselves, and there are no reports examining its expression in peritumoral supporting cells.…”

Section: Discussionmentioning

confidence: 99%

“…RHBDD2 was identified as a new gene responsible for drug resistance with cell–cell interactions, and clinical data also supported that the loss of RHBDD2 in supporting cells was suggested as a poor prognosis factor. RHBDD2 is a member of the rhomboid family of membrane-bound proteases and is known to be overexpressed in the advanced stages of breast cancers and colorectal cancers (Abba et al, 2009) (Lacunza et al, 2012) (Palma et al, 2020). RHBDD2 is also reported that its overexpression promotes chemoresistance and invasive phenotypes of rectal cancer (Palma et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Indirect CRISPR screening with photoconversion revealed key factors of drug resistance with cell–cell interactions

Sugita

Onishi

Nakayama

et al. 2022

Preprint

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Comprehensive screenings to clarify indirect cell–cell interactions, such as those in the tumor microenvironment, especially comprehensive assessments of supporting cells' effects, are challenging. Therefore, in this study, indirect CRISPR screening for drug resistance with cell–cell interactions was invented. The photoconvertible fluorescent protein Dendra2 was inducted to determine the drug resistance responsible factors of supporting cells with CRISPR screenings. Random mutated supporting cells co-cultured with leukemic cells induced drug resistance with cell–cell interactions. Supporting cells responsible for drug resistance were isolated with green-to-red photoconversion, and candidate genes were identified. Knocking out C9orf89, MAGI2, MLPH, or RHBDD2 in supporting cells reduced the ratio of apoptosis of cancer cells. In addition, the low expression of RHBDD2 in supporting cells, specifically fibroblasts, of clinical pancreatic cancer showed a shortened prognosis, and a negative correlation with CXCL12 was observed. Indirect CRISPR screening was established to isolate the responsible elements of cell–cell interactions. This screening method could reveal new mechanisms in all kinds of cell–cell interactions by revealing live phenotype-inducible cells, and it could be a new platform for discovering new targets of drugs for conventional chemotherapies.

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RHBDD2 overexpression promotes a chemoresistant and invasive phenotype to rectal cancer tumors via modulating UPR and focal adhesion genes

Cited by 7 publications

References 63 publications

NDRG4 sensitizes CRC cells to 5‑FU by upregulating DDIT3 expression

NDRG4 sensitizes CRC cells to 5‑FU by upregulating DDIT3 expression

Hyaluronic Acid-Modified Nanoparticles Self-Assembled from Linoleic Acid-Conjugated Chitosan for the Codelivery of miR34a and Doxorubicin in Resistant Breast Cancer

Indirect CRISPR screening with photoconversion revealed key factors of drug resistance with cell–cell interactions

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