One aspect of chemotherapy insensitivity and resistance results from induction of epidermal growth factor receptor (EGFR) internalization and initial DNA damage repair in response to DNA-damaging stimuli, such as cisplatin (CDDP). Previously, we found that leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1), as one of the natural ligands of EGFR, could combine with and down-regulate the expression of EGFR in bladder cancer cells. This finding interested us and we hypothesized that LRIG1 could be a novel candidate for facilitating cisplatin-induced bladder cancer cell lesions. To investigate this further, we overexpressed LRIG1 with an adenovirus vector in EJ/T24 bladder cancer cells and investigated total EGFR, nuclear expression of phosphorylated EGFR (pEGFR) and cell lesions with exposure to CDDP. CDDP-induced nuclear pEGFR levels accumulated with time and were decreased by LRIG1 overexpression. LRIG1-transduced cells treated with CDDP had more severe DNA damage, cellular apoptosis, growth inhibition and reversal of invasion. These preclinical studies indicate that LRIG1 may represent a new therapeutic approach to improve the response of bladder cancer to chemotherapy through a novel pathway.

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