A TGF‐β1 genetic variant at the miRNA187 binding site significantly modifies risk of HPV16‐associated oropharyngeal cancer

Abstract

TGF-β1rs1982073 polymorphism at the miRNA-187 binding site may alter TGF-β1 expression and function, and thereby this polymorphism (genotype CT/CC) increases cancer susceptibility. HPV16 L1 seropositivity is associated with the risk of oral squamous cell carcinoma (OSCC), including oropharyngeal squamous cell carcinoma (OPSCC) and oral cavity squamous cell carcinoma (OCSCC). Thus, we hypothesized that TGF-β1rs1982073 polymorphism at the miRNA-187 binding site combined with HPV16 L1 seropositivity may have a joint effect on OSCC susceptibility. We determined the genotypes of TGF-β1rs1982073 and HPV16 status in 325 OSCC subjects and 335 cancer-free controls in the non-Hispanic white population, and used logistic regression models to evaluate the joint effects on OSCC susceptibility. TGF-β1rs1982073 polymorphism (CT/CC genotype) combined with HPV16 L1 seropositivity increased the risk of OSCC via joint effects, particularly in OPSCC subjects who were never-smokers (OR, 165.9; 95% CI, 28.6–960.4) or never-drinkers (OR, 196.0; 95% CI, 28.2–1000.0), respectively. Younger subjects had a higher risk of OPSCC than older subjects (OR, 23.5; 95% CI, 6.3–87.0 vs. OR, 6.0; 95% CI, 1.7–17.9, respectively). The significant associations between this polymorphism and HPV16-associated OSCC and OPSCC were also observed. However, OCSCC subjects did not have similar results. Our findings suggest that the joint effects of TGF-β1rs1982073 and HPV16 L1 seropositivity can increase risk of HPV16-associated oral cancer, particularly in OPSCC subjects who are never-smokers, never-drinkers, and young. This result may help us understand the tumorigenesis process and improve early detection, which are critical for prevention and intervention strategies. However, larger studies are needed to validate our findings.

Epithelial-to-Mesenchymal Transition-Derived Heterogeneity in Head and Neck Squamous Cell Carcinomas

“…In nasopharyngeal carcinomas (NPC), TGF-β1 functions can be modulated from metastasis enhancer to tumor suppressor functions by the transcription factor FOXA1, showcasing dual functions of EMT regulators as will be discussed for EGF, too [ 69 ]. Furthermore, regulation of TGF-β1 expression and activity by microRNAs (miRNAs) can be altered, for example, through polymorphisms in miRNA-binding sites, resulting in enhanced susceptibility towards HPV16-induced oropharyngeal cancer [ 70 ]. Additionally, a role for the TGF family member TGF-β2 in the regulation of dormancy of disseminated HNSCC tumor cells in the bone marrow was described, which was dependent on TGF-β receptors I and III [ 71 ].…”

TGF-β1 and TGF-βR1 variants are associated with clinical outcomes in smoking-related head and neck cancer patients treated with chemoradiation through modulating microRNA-mediated regulation

“…Our previous findings [ 15 , 18 ] demonstrated a notable association between TGF-β1 rs1800470 and survival in patients with HPV16-positive oropharyngeal cancer following definitive radiotherapy. These findings were consistent with our present study and imply that this genetic variant could induce a functional alteration and potentially influence treatment responses, impacting clinical results.…”

MicroRNA-21 induces cisplatin resistance in head and neck squamous cell carcinoma

“…As an additional supplemental regulator, TGF-β can upregulate pre-miR-21 expression, while BMP6 (a member of the TGF-β family) can downregulate miR-21 expression [ 24 ]. These contrasting functions suggest that the members of the TGF-β family may establish an equilibrium state, which is disrupted within the tumour microenvironment because tumour cells can excessively express autocrine TGF-β1 [ 25 , 26 ], which can lead to further production of an abundance of miR-21 and generate a feed-forward loop in cancer progression.…”