Abstract
Proapoptotic tumor suppressor WWOX is upregulated in the early stage of cancer initiation, which probably provides limitation to cancer growth and progression. Later, WWOX protein is reduced to enhance cancer cell growth, migration, invasiveness and metastasis. To understand how WWOX works in controlling cancer progression, here we demonstrate that apoptotic stress mediated by ectopic WWOX stimulated cancer cells to secrete basic fibroblast growth factor (bFGF) in order to support capillary microtubule formation. This event may occur in the cancer initiation stage. Later, when WWOX loss occurs in cancer cells, hyaluronidase production is then increased in the cancer cells to facilitate metastasis. We determined that inhibition of membrane hyaluronidase Tyr216-phosphorylated Hyal-2 by antibody suppresses cancer growth in vivo. WWOX-negative (WWOX-) cells dodged WWOX+cells in the microenvironment by migrating individually backward to avoid physical contacts and yet significantly upregulating the redox activity of WWOX+parental cells or other WWOX+cell types for causing apoptosis. Upon detecting the presence of WWOX+cells from a distance, WWOX- cells exhibit activation of MIF, Hyal-2, Eph, and Wnt pathways, which converges to MEK/ERK signaling and enables WWOX- cells to evade WWOX+cells. Inhibition of each pathway by antibody or specific chemicals enables WWOX- cells to merge with WWOX+cells. In addition, exogenous TGF-β assists WWOX- cells to migrate collectively forward and merge with WWOX+cells. Metastatic WWOX- cancer cells frequently secrete high levels of TGF-β, which conceivably assists them to merge with WWOX+cells in target organs and secure a new home base in the WWOX+microenvironment. Together, loss of WWOX allows cancer cells to develop strategies to dodge, compromise and even kill WWOX-positive cells in microenvironment.
Highlights
Proapoptotic tumor suppressor WW domain-containing oxidoreductase, designated WWOX, FOR or WOX1, is known to limit cancer growth and metastasis[1,2,3,4,5]
By quantitative RT/PCR, HYAL1 and HYAL2 mRNA transcripts were significantly reduced in WWOXexpressing basal cell carcinoma (BCC) cells (Fig. 1b)
Tumor lesions showed that Hyal-2 was significantly upregulated in the WWOX knockdown BCC cells (Fig. 1d; ~100% increase)
Summary
Proapoptotic tumor suppressor WW domain-containing oxidoreductase, designated WWOX, FOR or WOX1, is known to limit cancer growth and metastasis[1,2,3,4,5]. WWOX is even crucial in maintaining physiological settings, rather than functioning in tumor suppression. Null mutations of WWOX/Wwox gene cause severe neural diseases Chou et al Cell Death Discovery (2019)5:97 spinocerebellar ataxia), metabolic disorders (including lipid, cholesterol, and glucose metabolism), disorder of sex differentiation, and early death in the newborns[2,6,7]. Spontaneous tumor formation is rarely found in the WWOX-deficient newborns. WWOX gene is one of the 5 recently discovered risk factors in Alzheimer’s disease[8]. WWOX interacts with specific cytosolic proteins, mainly functioning in normal cell physiology and death[1,2,3,4,5] and metabolism such as glycolysis, fatty acid degradation and acetyl-CoA generation[9]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call