Background　Increasing　evidence　indicates　an　etiological　role　of　human　papillomavirus　(HPV)　in　head　and　neck　cancers,　particularly　oropharyngeal　squamous　cell　carcinoma　(OPSCC).　However,　the　association　between　HPV　and　other　cancers,　including　esophageal　and　tongue　remains　unclear.　This　study　delineated　the　molecular　characteristics　of　HPV18　E6　and　E7　in　esophageal　(EC109　and　EC9706)　and　tongue　(Tca83)　cancer　cell　lines　with　reference　to　cervical　cancer　(HeLa).　Methods　We　analysed　the　HPV　transcription　profiles　of　esophageal　and　tongue　cancer　cells　through　Next-generation　RNA　sequencing,　and　the　role　of　HPV18　E6　and　E7　in　these　cells　was　assessed　via　siRNA　approach,　Western　blotting　and　immunofluorescence　assays.　Results　Overall,　the　HPV　transcription　profiles　of　esophageal　and　tongue　cancer　cells　mimicked　that　of　cervical　cancer　cells,　with　notable　disruption　of　E2,　and　expression　of　E6,　spliced　E6　(E6*),　E7,　E1　and　L1　transcripts.　As　with　cervical　cancer　cells,　p53　and　its　downstream　transactivation　target,　p21,　were　found　to　be　the　major　targets　of　E6　in　esophageal　and　tongue　cancer　cell　lines.　Intriguingly,　E7　preferentially　targeted　p130　in　the　two　esophageal　cancer　cell　lines,　instead　of　pRb　as　in　cervical　cancer.　Tca83　exhibited　an　E7　to　E6　transcript　ratio　comparable　to　HeLa　(cervix),　targeted　the　ERK1/2　and　MMP2　pathways,　and　was　dependent　on　E6　and　E7　to　survive　and　proliferate.　In　contrast,　both　the　esophageal　cancer　cell　lines　were　distinct　from　HeLa　in　these　aspects.　Conclusions　This　is　the　first　study　that　delineates　transcript　expression　and　protein　interaction　of　HPV18　E6　and　E7　in　esophageal　and　tongue　cancer　cell　lines,　suggesting　that　HPV　plays　a　role　in　inducing　these　cancers,　albeit　via　distinct　pathways　than　those　observed　in　cervical　cancer.