Expression of CD98hc in Pancreatic Cancer and Its Role in Cancer Cell Behavior

Daniela Bianconi; Elisabeth Fabian; Merima Herac; Markus Kieler; Johannes Thaler; Gerald Prager; Matthias Unseld

doi:10.7150/jca.70500

Expression of CD98hc in Pancreatic Cancer and Its Role in Cancer Cell Behavior

J Cancer. 2022 Apr 18;13(7):2271-2280. doi: 10.7150/jca.70500. eCollection 2022.

Authors

Daniela Bianconi¹, Elisabeth Fabian², Merima Herac³, Markus Kieler⁴, Johannes Thaler⁵, Gerald Prager¹, Matthias Unseld⁶

Affiliations

¹ Division of Oncology, Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
² Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
³ Department of Pathology, Medical University of Vienna, Austria.
⁴ Institute for Vascular Biology, Center for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria.
⁵ Division of Hematology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
⁶ Division of Palliative Medicine, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Abstract

Background: Cluster of differentiation 98 heavy chain (CD98hc) is a transmembrane protein, which functions both as a coreceptor of ß-integrins, enhancing intracellular integrin-dependent downstream signaling, and as a transporter of branched-chain and aromatic amino acids. As such, it is pivotal in cell cycle regulation and protection of oxidative, nutritional and DNA replication stress. Overexpression of CD98hc occurs widely in cancer cells and is associated with poor clinical prognosis. The role of CD98hc in pancreatic cancer remains to be elucidated. The aim of this study was to determine the expression of CD98hc in pancreatic ductal adenocarcinoma and to define its potential functional role in cancer cell biology. Methods: Immunohistochemical staining for CD98hc was performed on 222 tissue samples of patients with pancreatic ductal adenocarcinoma. The pancreatic cancer cell lines PANC-1 and BxPC-3 were used to determine the effect of CD98hc expression on cancer cell behavior using cell adhesion, cell trans-migration and cell spreading assays. Flow cytometry was performed to study the rate of apoptosis after detachment or serum starvation. shRNA-lentiviral constructs were used to knock down or reconstitute full length or mutated CD98hc. Results: Up to 20% of pancreatic ductal adenocarcinomas express CD98hc in the acinar cells (13%) and islet cells (20%) embedded in tumor tissue. Although expression of CD98hc in tumor tissue was not associated with a particular tumor stage or grade, our data show a trend towards longer overall survival of pancreatic cancer patients without CD98hc expression as compared to those with immunohistochemical positivity. In vitro downregulation of CD98hc in the pancreatic cancer cell lines PANC-1 and BxPC-3 significantly inhibits cell proliferation (p<0.05), self-renewal (p<0.05) and anchorage-independent growth (p<0.05). Conclusion: CD98hc is expressed in a remarkable percentage of pancreatic ductal adenocarcinomas. Due to its important role in cell behavior and malignant cell transformation, it may be a promising molecular target for potential new therapeutic approaches in pancreatic cancer in the future.

Keywords: BxPC-3; CD98hc; PANC-1; pancreatic ductal adenocarcinoma.