Expression of ER stress and autophagy‐related molecules in human non‐small cell lung cancer and premalignant lesions

Abstract

Stress that impairs endoplasmic reticulum (ER) function leads to an accumulation of unfolded or misfolded proteins in the ER (ER stress). Autophagy is a lysosomal pathway involved in the turnover of cellular macromolecules and organelles, which emerging data indicate that ER stress is also a potent inducer of autophagy. ER stress and autophagy are involved in human cancer. We examined the expression of ER stress-related proteins [GRP78 and C/EBP homologous protein (CHOP)] and autophagic proteins (Beclin-1 and LC3) in non-small cell lung carcinomas (NSCLCs), bronchioloalveolar carcinomas (BACs) and atypical adenomatous hyperplasias (AAHs) to understand their role in the NSCLC pathogenesis. The expression of GRP78 and CHOP, Beclin-1 and LC3 were analyzed using immunohistochemistry on tissue sections from 133 NSCLC (69 squamous cell carcinomas, 56 adenocarcinomas (AC) and eight other NSCLCs), 21 BAC and 9 AAH. Expression of GRP78 and Beclin-1 was correlated with low tumor stage (p < 0.001 and p 5 0.019, respectively) and longer survival (p 5 0.007 and p <0.001, respectively) by Kaplan-Meier analysis. However, CHOP was correlated with high tumor stage (p 5 0.038) and shorter survival (p 5 0.012). Expression of GRP78 and Beclin-1 was positively correlated (p 5 0.006). Our study showed that the expression of GRP78, CHOP, Beclin-1 and LC3 in lung cancer and its relation with clinicopathologic factors and patients survival. These results suggest that GRP78, CHOP and Beclin-1 may play an important role in tumorigenesis of lung AC and may serve as new prognostic indicators for outcome of the patients with NSCLC.

Expression Profile of Autophagy-related Markers in Localized Prostate Cancer: Correlation With Biochemical Recurrence After Radical Prostatectomy

“…Beclin1 and LC3 expressions were scored by the summation of the proportion of immunoreactive cells (0: 0%-9%, 1: 10%-49%, or 2: 50%-100%) and the staining intensity (0: no staining, 1: weak, 2: medium, or 3: strong), and a score of 4 or 5 was considered to represent strong expression, as previously described. 10 As previously described, 22 tumors with <10% cells with weak staining of mTOR were scored as 0, those with >10% cells with weak staining or <20% cells with intermediate-tostrong staining of mTOR were scored as 1, and those with >20% cells with intermediate-to-strong staining of mTOR were scored as 2, and a staining score of either 1 or 2 was considered to represent strong mTOR expression.…”

“…8,9 Furthermore, inconsistent findings have been reported with respect to whether the expression profile of autophagyrelated markers is associated with the prognosis of patients with malignant tumors. [10][11][12][13][14] In the field of PC research as well, a few studies assessed the significance of molecular markers involved in autophagy. [15][16][17] For example, Giatromanolaki et al 17 reported that the strong and extensive expression of LC3 in PC specimens was closely associated with the Gleason score, whereas Jiang et al 16 showed the significant impact of the elevated expression of a mitochondrion-associated autophagy inhibitor, leucine-rich pentatricopeptide repeat motifecontaining protein, on the prognosis of PC patients at a late stage with a poor prognosis.…”

“…However, the functional role of autophagy in carcinogenesis is still unclear, that is, the role of autophagy, as a prosurvival mechanism to protect cancer cells from various forms of cellular stress, is supported by most accumulated evidence, whereas, paradoxically, the disruption of autophagyassociated genes has been shown to contribute to accelerated tumorigenesis under some conditions. 8,9 In recent years, there have been several studies reporting that the expression profiles of molecular markers consisting of the autophagy pathway could be used as useful predictors of clinical courses in several types of human malignant tumor [10][11][12][13][14] ; however, limited information is available on the prognostic significance of autophagy-related proteins in patients with PC. [15][16][17] Considering these findings, we evaluated the expression patterns of multiple autophagy-related proteins, including autophagy-related gene 5 (Atg5), autophagyrelated gene 9 (Atg9), Beclin1, microtubule-associated protein light chain 3 (LC3), and UNC-51elike kinase 1 (ULK1), in RP specimens from 160 patients with localized PC to analyze the prognostic significance of these markers in this cohort of patients.…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…Cancer CHOP expression in tumors correlates with stage, malignancy, and low survival in patients (Kim et al 2012;Dalton et al 2013). The incidence of K-ras (G12V)-induced lung cancer is markedly enhanced in the absence of CHOP (Huber et al 2013), suggesting an anticancer activity of CHOP.…”

Clinical significance of GADD153 expression in stage I non-small cell lung cancer

“…In previous studies, increased expression of GADD153 correlated with a lower tumor stage in colon cancer and with a higher survival rate in melanoma (33,34). A further study on lung cancer demonstrated that GADD153 expression correlated with a larger tumor size, higher pathological T stage, higher TNM stage and shorter overall survival rate (35). Therefore, we focused on the expression of GADD153 in patients with stage I (3) primary NSCLC and its association with clinical outcome.…”