**4.3 HPV infection**

Human papillomavirus (HPV) is a kind of small DNA virus that causes cervix cancer in females and anal cancer in males [20]. As a sexually transmitted pathogen, HPV also infects the human oral cavity in forms of oral sex behaviors and openmouthed kissing. HPV, especially high-risk subtypes 16 and 18, is reported to have its role in the carcinogenesis of around one-third of oral cancer [21, 22]. Further, oncoprotein p16 is found over-expressed in oral cancer patients with high-risk HPV infection. Meanwhile, the relationship between HPV and oral cancer is not so strong when compared with oropharynx cancer, as studies showed that HPV-16 is found in 10–25% and HPV-18 in 14% of oral cancers [23]. Interestingly, HPV-positive oral cancers generate a more favorable outcome, possibly due to an enhanced anti-virus immune reaction. However, the role of HPV in oral cancer is far from clear [24].

#### **4.4 Others**

Besides, carcinogenesis of oral cancer is influenced by other factors namely betel quid chewing [25], poor diet and nutrition such as lack of fresh fruits and vegetables [26], poor oral hygiene [27], oral microbiome alteration [28], and genetic susceptibility [29].
