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Inhibition of hyaluronan synthase-3 decreases subcutaneous colon cancer growth by increasing apoptosis
Brian P Teng1, Melissa D Heffler, Eric C Lai
1Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263 USA. melissa.heffler@roswellpark.org
Abstract:
Hyaluronan (HA) and hyaluronan synthases (HAS) have been implicated in cancer growth and progression. We previously have shown that HAS3 and HA mediate tumor growth in SW620 colon cancer cells, but the mechanism remains poorly understood. In addition, the effect of HAS3 inhibition on tumor growth with other cells lines has not been explored. We therefore hypothesized that inhibition of HAS3 in highly tumorigenic HCT116 colon cancer cells would decrease tumor growth and that the underlying mechanism would involve altering proliferation and/or apoptosis. HAS3 expression was inhibited by transfection with siRNA; a scrambled sequence served as a control. Stable transfectants were injected into the flanks of nude mice and tumor growth followed for 30 days. Proliferation and apoptosis were then assessed in the harvested tumors. Results were compared using the Students' t-test and ANOVA where appropriate. siRNA transfection decreased HAS3 expression, protein production, and pericellular HA retention, and decreased in vivo tumor growth. Proliferation was unaffected in the HCT116 tumors, but increased slightly in the SW620 tumors. In contrast, HAS3 inhibition significantly increased apoptosis in all tumors. HAS3 inhibition decreases subcutaneous tumor growth by colon cancer cells and significantly increases apoptosis with less effect on proliferation. These data show that HAS3 and HA mediate colon cancer growth by inhibiting apoptosis.
Insights
Inhibiting hyaluronan synthase 3 (HAS3) in colon cancer cells reduces tumor growth by increasing apoptosis, not affecting proliferation. This highlights HAS3 as a target for colon cancer therapy.
Area of Science:
- Molecular Biology
- Cancer Research
- Biochemistry
Background:
- Hyaluronan (HA) and hyaluronan synthases (HAS) are linked to cancer progression.
- Previous studies showed HAS3 and HA promote tumor growth in SW620 colon cancer cells.
- The precise mechanism and effect of HAS3 inhibition in other cell lines remain unclear.
Purpose of the Study:
- To investigate the effect of inhibiting hyaluronan synthase 3 (HAS3) in highly tumorigenic HCT116 colon cancer cells.
- To determine if HAS3 inhibition decreases tumor growth and understand the underlying mechanisms involving proliferation and apoptosis.
Main Methods:
- HCT116 colon cancer cells were transfected with siRNA targeting HAS3 expression.
- Stable transfectants were used for in vivo tumor growth studies in nude mice over 30 days.
- Tumor proliferation and apoptosis were assessed post-harvest; statistical analysis included Student's t-test and ANOVA.
Main Results:
- siRNA-mediated HAS3 inhibition reduced HAS3 expression, protein levels, and pericellular HA.
- In vivo tumor growth was significantly decreased in HAS3-inhibited HCT116 cells.
- Apoptosis was significantly increased in tumors with HAS3 inhibition, while proliferation remained largely unaffected in HCT116 cells.
Conclusions:
- HAS3 inhibition effectively decreases subcutaneous colon cancer tumor growth.
- The primary mechanism involves a significant increase in apoptosis, with minimal impact on cell proliferation.
- HAS3 and HA play a crucial role in colon cancer growth by suppressing apoptosis, making HAS3 a potential therapeutic target.
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