Role of TXNDC5 in tumorigenesis of colorectal cancer cells: In vivo and in vitro evidence

Tan,Fengbo; Zhu,Hong; He,Xiao; Yu,Nanhui; Zhang,Xingwen; Xu,Haifan; Pei,Haiping

doi:10.3892/ijmm.2018.3664

Role of TXNDC5 in tumorigenesis of colorectal cancer cells: In vivo and in vitro evidence

Authors:
- Fengbo Tan
- Hong Zhu
- Xiao He
- Nanhui Yu
- Xingwen Zhang
- Haifan Xu
- Haiping Pei
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Affiliations: Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Department of Mammary, Hunan Cancer Hospital, Changsha, Hunan 410013, P.R. China, Department of Emergency, Hunan Provincial People's Hospital, Changsha, Hunan 410005, P.R. China, Department of Mammary and Thyroid, The First Affiliated Hospital of South China University, Hengyang, Hunan 421001, P.R. China
Published online on: May 9, 2018 https://doi.org/10.3892/ijmm.2018.3664
Pages: 935-945
Copyright: © Tan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Thioredoxin domain‑containing 5 (TXNDC5) is reportedly overexpressed in colorectal cancer (CRC) and is therefore considered an oncogene. However, the role of TXNDC5 in CRC tumorigenesis remains unclear. The present study aimed to explore the role of TXNDC5 in CRC tumorigenesis in vitro and in vivo under hypoxic and normoxic conditions. Analyses of patient tissue samples revealed a positive association between the expression of hypoxia‑inducible factor‑1α (HIF‑1α) or TXNDC5 and the TNM stage of CRC. In addition, a positive correlation between the expression levels of HIF‑1α and TXNDC5 was observed in CRC tissues. Furthermore, culturing RKO and HCT‑116 human CRC cell lines under hypoxic conditions significantly increased the expression levels of HIF‑1α and TXNDC5, whereas knockdown of HIF‑1α abolished the hypoxia‑induced expression of TXNDC5. Knockdown of TXNDC5 significantly decreased cell proliferation and colony formation, and increased apoptosis of both cell lines. Furthermore, knockdown of TXNDC5 markedly increased hypoxia‑induced reactive oxygen species (ROS) generation, and the expression of hypoxia‑induced endoplasmic reticulum stress (ER) markers (CCAAT‑enhancer‑binding protein homologous protein, glucose‑regulated protein 78 and activating transcription factor 4) and apoptotic markers (B‑cell lymphoma 2‑associated X protein and cleaved caspase‑8). In addition, the expression levels of TXNDC5 were significantly increased in tumor tissues compared with in adenoma and normal tissues in a mouse model of CRC tumorigenesis. In conclusion, the in vivo data demonstrated that TXNDC5 is overexpressed in CRC tissues, and this overexpression may be associated with unfavorable clinicopathological features. The in vitro data indicated that hypoxia may induce TXNDC5 expression via upregulating HIF‑1α; this effect promoted CRC cell proliferation and survival under hypoxic conditions, likely via inhibiting hypoxia‑induced ROS/ER stress signaling. These findings suggested that TXNDC5 functions as an important stress survival factor to maintain tumorigenesis of CRC cells under hypoxia by regulating hypoxia‑induced ROS/ER stress signaling. The present study provided novel insights into the role of TXNDC5 in the tumorigenesis of CRC.

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