Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma

Abstract

p62/SQSTM1 is a selective substrate of autophagy, and aberrant accumulation of p62 has been observed in various pathological conditions. To understand the roles p62 plays in non-small-cell lung cancer (NSCLC), we carried out immunohistochemical analyses of p62 expression in a cohort of patients with annotated clinicopathological data. As analyses of murine and human hepatocellular carcinomas suggested a correlation between p62 and Nrf2 accumulations, we also examined NRF2 expression in the same cohort. The expression of NRF2 and p62 was examined by immunohistochemical methods in 109 NSCLC cases, which included patients with adenocarcinoma (n = 72), squamous cell carcinoma (n = 31), and large cell carcinoma (n = 6). Accumulation of NRF2 and p62 was detected in 34% and 37% of NSCLC patients, respectively. The accumulations of p62 and NRF2 did not correlate with each other, but both were associated with worse lung cancer-specific survival (P = 0.0003 for NRF2; P = 0.0130 for p62). NRF2 status had an impact on NSCLC prognosis irrespective of histology types, but p62 status did so particularly in adenocarcinoma (P = 0.037). Multivariate analysis indicated that positive immunoreactivities of NRF2 and p62 were both independent factors predicting worse lung cancer-specific survival (P < 0.0001 for NRF2 and P = 0.04 for p62). This study revealed that both NRF2 and p62 are independent prognostic factors for NSCLC. The prognostic impact of p62 status was pronounced in adenocarcinoma patients, suggesting that molecular mechanisms underlying cancer evolution differ between adenocarcinoma and squamous cell carcinoma. (Cancer Sci 2012; 103: 760-766) N on-small-cell lung cancer (NSCLC), which comprises mainly adenocarcinoma and squamous cell carcinoma, is one of the most common human cancers.(1) Despite rigorous endeavors to develop anticancer therapies, the prognosis of lung cancer patients still remains poor. To predict recurrence after surgery and to judge indications of additional therapies appropriately, clinical and biological markers have long been sought.The Keap1-Nrf2 system plays a central role in protecting cells from electrophilic and oxidative stresses.(2) Under unstressed conditions, Keap1 ubiquitinates Nrf2, and Nrf2 is degraded by the proteasome. Upon exposure to the stimuli, Keap1 is inactivated, and stabilized Nrf2 induces the transcription of many cytoprotective genes. Somatic mutations in the NRF2 or KEAP1 gene that cause constitutive stabilization of NRF2 have been found in many human cancers.(3-9) Reduced expression of KEAP1 due to KEAP1 methylation has been suggested as another mechanism for NRF2 stabilization.(10,11) NRF2 stabilization and subsequent accumulation contribute to the poor prognosis of NSCLC patients. (6,7) This is because NRF2 confers resistance to anticancer therapies and an aggressive proliferative tendency on cancer cells. (10,12) Recently, still another cause for the constitutive stabilization of NRF2 in cancer cells was reported. One of the selective substrates for autophagy, (13,1...

The peiminine stimulating autophagy in human colorectal carcinoma cells via AMPK pathway by SQSTM1

“…In cancer cells, the expression of autophagy related proteins is lower than that in normal cells, if cells fail to execute autophagy, the tumor progresses [16,17]. Previous studies identified that insufficient activation of autophagy-related signaling pathway in cancer cells results in insufficient autophagy, which further induces malignant phenotype [18,19]. Based on the data revealed in Fig.3, the signaling pathway of peiminine-induced elevation in autophagic flux involves repressing phosphorylation of mTOR through inhibiting upstream of PI3K/Akt and AMPK.…”

NRF2 immunolocalization in human breast cancer patients as a prognostic factor

“…Human lung carcinoma tissue was used as a positive control for NRF2, p62, and NQO1 immunostaining (Inoue et al 2012). As a negative control, normal rabbit, mouse, or goat IgG was used instead of the primary antibody in this study.…”

“…Moreover, recent data also indicate that p62/SQSTM1 plays an important role in the accumulation of NRF2 in carcinoma cells (Komatsu et al 2010, Inami et al 2011). An association between NRF2 accumulation and adverse clinical outcome of patients has been reported in lung (Solis et al 2010, Inoue et al 2012, gallbladder (Wang et al 2010), and ovarian (Konstantinopoulos et al 2011) carcinomas. These findings indicate that NRF2 is possibly involved in the growth and/or progression of these carcinomas.…”

Kinetic, Thermodynamic, and Structural Characterizations of the Association between Nrf2-DLGex Degron and Keap1

“…NRF2 protects cancer cells against stress from the microenvironment or anticancer drugs and confers radiation resistance on cancer cells (20)(21)(22). Indeed, patients with somatic mutations in NRF2 or KEAP1 have a poor prognosis (19,(22)(23)(24)(25).…”