Radiation-Induced Overexpression of TGFβ and PODXL Contributes to Colorectal Cancer Cell Radioresistance through Enhanced Motility

Abstract

The primary cause of colorectal cancer (CRC) recurrence is increased distant metastasis after radiotherapy, so there is a need for targeted therapeutic approaches to reduce the metastatic-relapse risk. Dysregulation of the cell-surface glycoprotein podocalyxin-like protein (PODXL) plays an important role in promoting cancer-cell motility and is associated with poor prognoses for many malignancy types. We found that CRC cells exposed to radiation demonstrated increased TGFβ and PODXL expressions, resulting in increased migration and invasiveness due to increased extracellular matrix deposition. In addition, both TGFβ and PODXL were highly expressed in tissue samples from radiotherapy-treated CRC patients compared to those from patients without this treatment. However, it is unclear whether TGFβ and PODXL interactions are involved in cancer-progression resistance after radiation exposure in CRC. Here, using CRC cells, we showed that silencing PODXL blocked radiation-induced cell migration and invasiveness. Cell treatment with galunisertib (a TGFβ-pathway inhibitor) also led to reduced viability and migration, suggesting that its clinical use may enhance the cytotoxic effects of radiation and lead to the effective inhibition of CRC progression. Overall, the results demonstrate that downregulation of TGFβ and its-mediated PODXL may provide potential therapeutic targets for patients with radiotherapy-resistant CRC.

Targeting SIRT1 synergistically improves the antitumor effect of JQ-1 in hepatocellular carcinoma

“…Similar to the traditional view, after JQ-1 treatment, the expression of many oncogenes was downregulated, but we also found abnormally high expression of several key genes that may lead to acquired resistance to JQ-1. PubMed and Web of Science were used to explore the biological roles of TSGA10, FOS, FGF18, MGAT5, EFNB2, and PODXL in cancer research [ [40] , [41] , [42] ]. However, only a small number of cancer studies have focused on these specific genes, which limits our further research.…”

Changes in Tumor Immune Microenvironment after Radiotherapy Resistance in Colorectal Cancer: A Narrative Review

“…1a). It was found that radiation-resistant CRC increased the expression of TGF-β and the cell surface glycoprotein podocalyxin-like protein (PODXL) to promote tumor invasion and metastasis [23]. Furthermore, CRC patients with high TGF-β and PODXL expression have been shown to have worse prognosis [24][25][26].…”

Multifaceted role of RNA editing in promoting loss-of-function of PODXL in cancer

“…Association studies suggested that PODXL is a potential biomarker for cancer diagnosis and prognosis in multiple cancers ( Borg et al., 2016 ; Kusumoto et al., 2017 ; Lee et al., 2017 ; Taniuchi et al., 2018 ; Zhang et al., 2019 ; He et al., 2020 ). In addition, PODXL plays important role in cancer metastasis by promoting cell migration ( Lin et al., 2014 ; Kusumoto et al., 2017 ; Lee et al., 2017 , 2021 ), cell invasion ( Wu et al., 2013 ; Lin et al., 2014 ; Chan et al., 2016 ; Kusumoto et al., 2017 ), cell extravasation ( Fröse et al., 2018 ), immune evasion ( Amo et al., 2015 ), and chemoresistance ( Huang et al., 2015 ; Zhou et al., 2015 ; Lee et al., 2017 ; Tamayo-Orbegozo et al., 2020 ). Therefore, PODXL is also a valuable therapeutic target for cancer metastasis ( Snyder et al., 2015 ; Chijiiwa et al., 2016 ).…”