Molecular Chaperones as a Common Set of Proteins That Regulate the Invasion Phenotype of Head and Neck Cancer

Abstract

Purpose: The goal of this study was to establish a common set of molecules that regulate cell invasion in head and neck cancer (HNC).Experimental Design: Five invasive sublines derived from HNC cell lines were established using the Matrigel selection method. Proteomic technology, MetaCore algorithm, and reverse transcriptase-PCR methods were used to search for molecules that contribute to the invasion phenotype. Cellular functional analyses and clinical association studies were applied to examine the significance of the molecules.Results: Fifty-two proteins were identified in more than two of the four independent proteomic experiments, including 10 (19%) molecular chaperones. Seven chaperones were confirmed to be differentially expressed in five sublines, Hsp90a, Hsp90b, Hsp90-B1/Gp96, Hsp70-A5/Grp78, and HYOU1, that upregulate, whereas Hsp60 and glucosidase-a neutral AB (GANAB) downregulate. Four molecules were further investigated. In all cell lines, knockdown of Hsp60 or GANAB and silencing of Gp96 or Grp78 considerably enhanced or reduced cell migration and invasion, respectively. Clinical association studies consistently revealed that low levels of Hsp60 or GANAB and high levels of Gp96 or Grp78 are significantly associated with advanced cancer (P < 0.001 to P ¼ 0.047, respectively, for the four molecules) and poor survival (P < 0.001 to P ¼ 0.025, respectively, for the four molecules).Conclusion: Our study defined molecular chaperones as a common set of proteins that regulate the invasion phenotype of HNC. Loss of the tumor suppression function of Hsp60 or GANAB and acquisition of the oncogenic function of Gp96 or Grp78 contribute to aggressive cancers. These molecules may serve as prognostic markers and targets for cancer drug development.

An integrated computational and experimental study uncovers FUT 9 as a metabolic driver of colorectal cancer

“…Interestingly, we found downregulation of the glucosidase II alpha subunit GANAB (fold change = −11.28) and Core2/Core4 beta‐1,6‐N‐acetylglucosaminyltransferase GCNT3 (fold change = −3.55) (Appendix Fig S3A). Downregulation of both these genes has been previously shown to lead to enhanced cell migration and invasion, resulting in aggressive cancers, consistent with our results showing FUT9 knockdown leads to increased colony formation and cell migration (Fig 3D and F) (Huang et al , 2006; Chiu et al , 2011). Previous studies in colorectal cancer have shown that higher levels of core 1 glycans, T antigen, and Tn antigen are the most predominantly observed O‐glycosylation changes (Holst et al , 2015).…”

Modulation of Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Function by Hypoxia-Upregulated Protein 1

“…HYOU1 is expressed in many different cell types and can be upregulated by various cellular conditions, including hypoxia and ER stress (32,33). Furthermore, HYOU1 is upregulated in some human cancers, including head and neck and breast cancers (34,35). The HYOU1 transcript was originally cloned from astrocytes under hypoxic conditions (36), which makes it a protein relevant to KSHV biology, since hypoxia plays a role in the KSHV life cycle (37).…”

Active heat shock transcription factor 1 supports migration of the melanoma cells via vinculin down-regulation

“…Cell migration is a complex process that integrates different protein-protein interactions and signaling events, and includes focalized adhesion dynamics and the remodeling of the structure of the actomyosin skeleton [9]. The potential role of HSPs and other chaperones in this process might be considered because they are involved both in functions of cytoskeleton [22] and metastasis [4,25,38]. Hence, we can not exclude that HSF1-regulated HSPs play a role in our experimental model.…”