RHBDD2 overexpression promotes a chemoresistant and invasive phenotype to rectal cancer tumors via modulating UPR and focal adhesion genes.,Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

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RHBDD2 overexpression promotes a chemoresistant and invasive phenotype to rectal cancer tumors via modulating UPR and focal adhesion genes.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( IF 4.2 ) Pub Date : 2020-04-25 , DOI: 10.1016/j.bbadis.2020.165810
S Palma ₁ , C I Raffa ₂ , M B Garcia-Fabiani ₃ , V A Ferretti ₁ , A Zwenger ₄ , P V Perez Verdera ₄ , A Llontop ₅ , E Rojas Bilbao ₅ , V Cuartero ₆ , M C Abba ₁ , E Lacunza ₁

Affiliation

The current standard of care for locally advanced rectal cancer (RC) is neoadjuvant radio-chemotherapy (NRC) with 5-fluorouracil (5Fu) as the main drug, followed by surgery and adjuvant chemotherapy. While a group of patients will achieve a pathological complete response, a significant percentage will not respond to the treatment. The Unfolding Protein Response (UPR) pathway is generally activated in tumors and results in resistance to radio-chemotherapy. We previously showed that RHBDD2 gene is overexpressed in the advanced stages of colorectal cancer (CRC) and that it could modulate the UPR pathway. Moreover, RHBDD2 expression is induced by 5Fu. In this study, we demonstrate that the overexpression of RHBDD2 in CACO2 cell line confers resistance to 5Fu, favors cell migration, adhesion and proliferation and has a profound impact on the expression of both, the UPR genes BiP, PERK and CHOP, and on the cell adhesion genes FAK and PXN. We also determined that RHBDD2 binds to BiP protein, the master UPR regulator. Finally, we confirmed that a high expression of RHBDD2 in RC tumors after NRC treatment is associated with the development of local or distant metastases. The collected evidence positions RHBDD2 as a promising prognostic biomarker to predict the response to neoadjuvant therapy in patients with RC.

中文翻译：

RHBDD2的过表达通过调节UPR和黏着斑基因来促进直肠癌肿瘤的化学抗性和侵袭性表型。

当前局部晚期直肠癌（RC）的护理标准是以5-氟尿嘧啶（5Fu）为主要药物的新辅助放化疗（NRC），然后进行手术和辅助化学疗法。虽然一组患者将达到病理完全缓解，但很大一部分患者对治疗无反应。展开蛋白反应（UPR）途径通常在肿瘤中被激活，并导致对放射化学疗法的抵抗。我们以前表明，RHBDD2基因在结直肠癌（CRC）的晚期阶段过表达，并且可以调节UPR途径。此外，RHBDD2表达是由5Fu诱导的。在这项研究中，我们证明了CACO2细胞系中RHBDD2的过表达赋予对5Fu的抗性，有利于细胞迁移，粘附和增殖，对UPR基因BiP，PERK和CHOP的表达以及对细胞粘附基因FAK和PXN都有深远的影响。我们还确定了RHBDD2与BiP蛋白（主要的UPR调节剂）结合。最后，我们证实NRC治疗后RC肿瘤中RHBDD2的高表达与局部或远处转移的发生有关。收集的证据将RHBDD2定位为有前景的预后生物标志物，以预测RC患者对新辅助疗法的反应。

更新日期：2020-04-25

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