P62/Ubiquitin IHC Expression Correlated with Clinicopathologic Parameters and Outcome in Gastrointestinal Carcinomas

Abstract

P62 and ubiquitin are small regulatory proteins demonstrated to have implications in the prognosis and survival of various malignancies including: hepatocellular, breast, ovarian, and some gastrointestinal carcinomas. Several trials studied the link of their activity to the extrinsic apoptosis pathway and showed that their autophagy modification has a critical stand point in tumorigenesis. These findings explain their vital role in controlling the process of cell death and survival. It has been shown recently that p62 and ubiquitin overexpression in different types of cancers, such as triple negative breast and ovarian cancers, have directly correlated with incidence of distant metastases. We aim to evaluate p62/ubiquitin expression in gastrointestinal carcinomas of gastric, colonic, and pancreatic origin, and correlate with annotated clinicopathologic data. In gastric carcinoma (61), positive p62 nuclear expression was noted in 57% and cytoplasmic in 61%, while positive ubiquitin was nuclear expressed in 68.8%, and cytoplasmic in 29.5%. In colon carcinoma (45), positive p62 nuclear expression was noted in 29% and cytoplasmic in 71%, while positive ubiquitin was nuclear in 58% and cytoplasmic in 44%. In pancreatic cancer (18), positive p62 nuclear expression was noted in 78% and cytoplasmic in 56%, while positive ubiquitin was nuclear in 83% and cytoplasmic in 72%. Normal gastric (6), colon (4), and pancreatic (4) tissues were negative for both P62 and ubiquitin (nuclear and cytoplasmic staining <20%). Ubiquitin high expression was associated with more lymph node metastases in colon (4.14 vs 1.70, P = 0.04), and pancreatic adenocarcinomas (3.07 vs 0.33, P = 0.03). Also, ubiquitin high expression was associated with worse pancreatic adenocarcinoma overall survival (1.37 vs 2.26 mos, P = 0.04). In addition, gastric cancer patients with high p62 expression tend to have more poorly differentiated grade when compared to those with low expression (21 vs 17, P = 0.04) but less lymph node metastases (2.77 vs 5.73, P = 0.01). P62 and ubiquitin expression did not correlate with other clinicopathologic parameters in gastric, colon or pancreatic denocarcinomas. The results suggest that p62 and ubiquitin are highly expressed in gastric, colonic, and pancreatic carcinomas. High ubiquitin expression was noted to have an impact on number of lymph node metastases in patients with colon and pancreatic adenocarcinomas, but on overall survival only in patients with pancreatic adenocarcinoma. Also, P62 high expression is correlated with poor differentiation, but less lymph node metastases, in gastric carcinoma.

Hepatocellular carcinomas with intracellular hyaline bodies have a poor prognosis

“…Since p62 is an autophagy substrate, a high level of p62 in the cytoplasm may indicate suppressed or defective autophagy, resulting in altered NF‐kappa B‐related gene expression and promotion of tumorigenesis . Furthermore, p62 overexpression presumably related to an autophagy defect has been found in a number of human cancers . In a recent study, a stronger cytoplasmic expression of p62 was found in HCC compared with non‐neoplastic liver.…”

“…MDBs only 17 ( related to an autophagy defect has been found in a number of human cancers. [28][29][30][31][32][33][34] In a recent study, a stronger cytoplasmic expression of p62 was found in HCC compared with non-neoplastic liver. Therefore, p62 has been proposed as a novel tumour marker for HCC.…”

Pan-Bcl-2 inhibitor Obatoclax is a potent late stage autophagy inhibitor in colorectal cancer cells independent of canonical autophagy signaling

“…P62 is a scaffold protein involved in a variety of cellular processes including NF-kB-signaling [ 31 , 50 , 51 ]. Recently, a correlation of p62 expression with clinicopathologic parameters has been shown for prostate cancer and gastrointestinal carcinoma [ 52 , 53 ]. Under obatoclax treatment we observe an accumulation of p62, which is indicative for a late stage autophagy inhibition, since the scaffold protein is trapped in the autophagic vesicle.…”

p62/SQSTM1—Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer

“…p62 is ubiquitously expressed in various cell types , mainly in the cytoplasm, and is also present in the nucleus, autophagosomes, and lysosomes . p62 is overexpressed in many types of human cancer, including hepatocellular carcinoma (HCC) , intrahepatic cholangiocarcinoma , pancreatic cancer , lung cancer , oral, head and neck cancer , esophageal cancer , gastric cancer , colon cancer , breast cancer , prostate cancer , melanoma , endometrial cancer , ovarian cancer , and kidney cancer , as well as chronic liver diseases, such as alcoholic and nonalcoholic steatohepatitis (ASH, NASH) that increase HCC risk . Therefore, a p62‐encoding DNA plasmid vaccine may be useful for cancer immunotherapy .…”