RESUMO
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.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana/genética , Neoplasias Retais/terapia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Antimetabólitos Antineoplásicos/farmacologia , Células CACO-2 , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Fluoruracila/farmacologia , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Adesões Focais/efeitos dos fármacos , Células HCT116 , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Metástase Linfática , Proteínas de Membrana/metabolismo , Terapia Neoadjuvante/métodos , Paxilina/genética , Paxilina/metabolismo , Ligação Proteica , Neoplasias Retais/genética , Neoplasias Retais/metabolismo , Neoplasias Retais/patologia , Transdução de Sinais , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismoRESUMO
Secreted mucins constitute a crucial part of the gel that protects respiratory and digestive epithelia, being MUC2/Muc2 the predominant gel-forming mucin of the intestine while MUC5AC/Muc5ac is one of the gel-forming mucins most expressed at the airways. In this study, we have analyzed Muc2 and Muc5ac during rat development by using immunohistochemistry, Western blotting and RT-PCR. We demonstrated that rat Muc2 was expressed in fetal intestinal goblet cells of surface epithelium of villi and developing Lieberkühn crypts. In neonates and adults, Muc2 was expressed at luminal goblet cells of small and large intestine and at gastric mucous and glandular cells. Muc5ac protein was observed in embryonic gastric and lung samples; expression increased during development and postnatal and adult life. After birth, a low reaction was detected at the tracheal surface epithelium and glands, which increased in adults.
Assuntos
Trato Gastrointestinal/metabolismo , Expressão Gênica , Mucina-5AC/genética , Mucina-2/genética , Ratos/genética , Sistema Respiratório/metabolismo , Animais , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário , Trato Gastrointestinal/crescimento & desenvolvimento , Mucina-5AC/metabolismo , Mucina-2/metabolismo , Ratos/crescimento & desenvolvimento , Ratos/metabolismo , Sistema Respiratório/crescimento & desenvolvimentoRESUMO
Over the last few years rhomboid genes have gained interest because of its association with cancer and neurodegenerative diseases. In previous studies, we demonstrated that human RHBDD2 is over-expressed in the advanced stages of breast and colorectal cancers, suggesting a favorable role in cell proliferation. So far little is known about the expression of RHBDD2 in other tissues and other species, and because of similarities between cancer and embryonic cells, this study focused on the evaluation of Rhbdd2 expression in embryonic and adult rat tissues. By IHC and RT-PCR, Rhbdd2 was identified in early stages of most tissues analyzed, with high expression in brain, spinal cord, kidney and embryonic skin. In adult tissues, the expression remained elevated while salivary glands became positive. Furthermore, Rhbdd2 showed a high expression in the most proliferative stages of the rat mammary gland. Indeed, similar findings were observed in the mouse mammary epithelial cell line HC11, in which Rhbdd2 resides in the Golgi apparatus, and at different stages of mouse mammary gland development. Therefore, Rhbdd2 would be implicated in embryonic and adult tissue proliferation.