Level of MMP-12 appears to be highly expressed in a wide range of cancers, including colorectal, gastric, skin nasopharyngeal and lung cancer [15-20]. A study was carried out to identify expression of LIFR, PIK3R1 and MMP- 12 in gall bladder carcinoma. This study validated MMP-12 as a significant prognostic biomarker in this rare and aggressive tumour [21]. Another study was conducted to analyse the expression of MMP-12 level in patients presenting with laryngeal squamous cell carcinoma. There was a poorer degree of tumour differentiation as the expression of MMP-12 went higher [22]. Elevated levels of MMP-12 were also correlated with pathological stage and metastasis of lung adenocarcinoma. Hence, targeting MMP-12 for the treatment of lung adenocarcinoma seemed promising. In addition to this, high expression of MMP-12 was observed in oesophageal squamous cell carcinoma compared to normal epithelial cell [23]. Due to its functional properties and its role in tissue destructive disease, MMP 12 can be used as a biomarker for various oral diseases [24]. It plays a significant part in tumorigenesis and progression. This includes tumour growth, migration, invasion and tumour metastasis [12, 25, 26]. MMP-12 is recommended as a diagnostic biomarker for OSCC due to its significant sensitivity and specificity [12].
The current study consisted of participants with a minimum age of 18 years and maximum age of 78 years with the mean age of 36.42 13.60 years. The mean age between OSF, OSCC and control groups was found to be significant. Statistical analysis was applied to observe the relationship between salivary MMP-12 expression and age of participants including both cases and controls group. The results demonstrated a statistically significant direct relationship between the two variables which explains that as the age increases, MMP-12 expression in saliva increases. In contrast to our findings, lower salivary MMP-12 levels were reported in a study in individuals aged 40-60 years as compared to individuals under 40 years [24].
A higher proportion (56%) of research participants were males whereas 44% were females. A statistically significant difference was observed in salivary MMP-12 expression among genders, implying higher mean expression of salivary MMP-12 in males as compared to females. However, no difference in salivary MMP-12 was observed between males and females in a study focusing on MMP-12 levels in patients with periodontal inflammation [24].
The study also illustrates the oral habits of participants. Majority of the participants were betel nut consumers followed by patients reporting tobacco smoking as their oral habit. A comparison was made between distinct oral habits and salivary MMP-12 expression. A significant difference was observed between the MMP-12 expression of individuals with distinct oral habits. Smokeless tobacco consumers demonstrated higher MMP-12 expression compared to other oral habits. However, individuals who reported tobacco and betel nut as their oral habit demonstrated lower MMP-12 expression comparatively. In contrast to the results mentioned, another study evidences a non-significant difference in MMP-12 expression among patients with different oral habits, including smoking, alcohol and betel nut chewing [27].
The results of the current study demonstrated a statistically significant difference in salivary MMP-12 expression in OSF and OSCC group as compared to healthy participants. Cases groups (OSF and OSCC) showed higher salivary MMP-12 expression and lower expression was observed in the control group. The results coincide with a previous study which indicated a high association of salivary protease spectrum with oral health status [28]. It demonstrated increased proteases levels in OSCC patients as compared to patients presenting with other oral diseases. MMP- 12 was detected only in the saliva of patients with OSCC along with other MMPs, such as MMP-1, MMP-2, MMP-3, MMP-10 and MMP-13. In addition to this, MMP-1, MMP-2, MMP-10 and MMP-12 were also observed to be significantly increased in patients with OSCC in comparison to healthy patients and patients with oral benign masses (OBM) and mild chronic periodontitis (CPD). The concentration of salivary MMP-12 in OSCC patients demonstrated in this study is around 1300 pg.ml-1 which is comparatively more than healthy (700 pg.ml-1), oral benign mass (900 pg.ml-1) and chronic periodontal disease patients (900 pg.ml-1) [28].
A cohort study carried out in Sweden on 436 participants aimed to investigate salivary MMP-12 levels about various aspects of oral health. The influence of non-disease covariates on MMP-12 levels was also assessed. The results revealed an association between MMP-12 levels and percentage of gingival pockets 4mm. The study concluded that MMP-12 reflect the various aspect of periodontal disease and the levels are contrarily affected by the presence of tumour [24]. The results of this study also corroborate the results of our study in which MMP-12 levels are affected in the presence of the tumor.
A study was conducted to compare the MMP12 level in patients presenting with OSCC and verrucous carcinoma (VC) in tissue samples. The study results showed that VCs were devoid of epithelial MMP-12 expressions compared to SCC [29]. Another study was undertaken to estimate serum MMPs levels in OSCC patients compared to healthy participants. Serum level of MMP-12 was notably arisen in OSCC patients as compared to healthy participants [12].
MMP-12 expression found elevated in patients with chronic periodontitis with identification of CD68+ CD14+CD64+ cells [24]. Also, the expression of MMP 12 in tissue sample goes high in patients with extracapsular spread compared to those without extracapsular spread[20]. Hence, it may be a useful predictive marker for extracapsular spread (ECS) in head and neck tumours[20].
In recent years, the prevalence of OSF has increased from 8.3/105 to 16.2/105 [30, 31]. The rate of malignant transformation to oral cancer is 9.13% and there’s 29.26 times higher risk in OSF patients as compared to non-OSF patients [32, 33]. In Pakistan, OSF is contemplated as a public health concern as oral malignancies are one of the most common malignancies reported [34]. Also, oral habits like tobacco smoking and consumption of betel nut and smokeless tobacco are major risk factors of OSF and are fairly common in Pakistan. Studying the role of several markers present in saliva will help in devising a non-invasive investigation for OSF diagnosis, which will ultimately result in early diagnosis of OSF and prevent it from advancing to OSCC if treated promptly. Since OSF is an oral potentially malignant disorder and is fairly common in our part of the world, we’ve studied the expression of MMP-12 in OSF patients along with OSCC patients.
Statistically, a significant difference in salivary MMP-12 level was observed in OSF patients in comparison with controls. OSF patients demonstrated higher MMP-12 levels as compared to controls. However, in comparison with salivary MMP-12 in OSCC, salivary MMP-12 in OSF demonstrated lower expression explaining the increase in MMP-12 expression as an oral potentially malignant disorder (OSF) drifts towards malignancy (OSCC). Since the significant difference in salivary MMP-12 levels is observed between OSF and OSCC, this investigation may serve as a useful non-invasive device for differentiating OSCC from specifically last stage OSF in which patients present with nil mouth opening and the surgeon suspects a lesion intraorally.