Calnexin, an ER-induced protein, is a prognostic marker and potential therapeutic target in colorectal cancer

Abstract

BackgroundColorectal cancer (CRC) is a leading cause of cancer mortality in the Western world and commonly treated with genotoxic chemotherapy. Stress in the endoplasmic reticulum (ER) was implicated to contribute to chemotherapeutic resistance. Hence, ER stress related protein may be of prognostic or therapeutic significance.MethodsThe expression levels of ER stress proteins calnexin, calreticulin, GRP78 and GRP94 were determined in n = 23 Stage II and III colon cancer fresh frozen tumour and matched normal tissue samples. Data were validated in a cohort of n = 11 rectal cancer patients treated with radiochemotherapy in the neoadjuvant setting. The calnexin gene was silenced using siRNA in HCT116 cells.ResultsThere were no increased levels of ER stress proteins in tumour compared to matched normal tissue samples in Stage II or III CRC. However, increased calnexin protein levels were predictive of poor clinical outcome in the patient cohort. Data were validated in the rectal cancer cohort treated in the neoadjuvant setting. Calnexin gene-silencing significantly reduced cell survival and increased cancer cell susceptibility to 5FU chemotherapy.ConclusionIncreased tumour protein levels of calnexin may be of prognostic significance in CRC, and calnexin may represent a potential target for future therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0948-z) contains supplementary material, which is available to authorized users.

Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers

“…Clinical evidences of such phenomenon are almost exclusively limited to breast cancers ( Table 4 ). 49 , 52 , 113 , 114 , 115 Indeed, expression of the UPR sensors and their downstream partners are correlated with resistance to tamoxifen, thereby leading to decreased time to recurrence and poor survival. 52 Interestingly, opposite effects are observed with the expression of XBP1u and XBP1s.…”

Hypoxia and Selective Autophagy in Cancer Development and Therapy

“…Moreover, CNX, another component implicated in hypoxia-induced mitophagy, is highly increased in cancer cells. This characteristic could render CNX a valuable prognosis marker (Lakkaraju and van der Goot, 2013 ; Kobayashi et al, 2015 ; Ryan et al, 2016 ; Ma et al, 2017 ). On the other hand, miR-137 acts as a tumor suppressor as evidenced in various cancer cell types (Neault et al, 2016 ; Chen T. et al, 2017 ; Ding F. et al, 2018 ).…”

Antigen processing and immune regulation in the response to tumours

“…Exposure of CRT at the cell surface promotes phagocytosis and engulfment by macrophages, resulting in destruction of tumour cells by immunogenic cell death . Interestingly, like CRT, the additional cellular role of CNX in ER stress has been implicated in cancer, with an increase in CNX expression linked with poor prognosis in colorectal cancer, and shown to be a diagnostic marker in lung cancer . The reduced expression of the thiol oxidoreductase, ERp57, that aids the formation of disulphide bonds to form the PLC, was shown to be an independent predictor of overall survival in cervical carcinoma and both the reduction and loss of ERp57 are correlated with progression of gastric cancer …”