HSP70 and mucin 5B: novel protein targets of N,N′‐dinitrosopiperazine‐induced nasopharyngeal tumorigenesis

Abstract

N,N′-Dinitrosopiperazine (DNP) induces nasopharyngeal carcinoma (NPC) and shows organ specificity to the nasopharyneal epithelium. To investigate its mechanism, the rat NPC model was inducd using DNP. Rat NPC and normal nasopharyngeal cells were obtained from the NPC model using laser capture. The total proteins from these cell samples were separated with two-dimension polyacrylamide gel electrophoresis techniques, and highly expressed proteins (> five-fold) were analyzed using matrix-assisted laser desorption/ionization time of flight and bioinformatics. The results showed that HSP70 and mucin 5B expression increased not only in rat NPC but also in atypical hyperplasia nasopharyngeal tissues, a precancer stage of NPC. High-expression of heat shock protein 70 (HSP70) and mucin 5B was further supported by western blot analysis. T he nonviral exposure most consistently and strongly associated with risk of nasopharyngeal carcinoma (NPC) is the consumption of salt-preserved fish, a traditional staple food in several NPC-endemic areas.(1) In studies of Chinese populations, the relative risk of NPC is associated with weekly consumption, compared with no or rare consumption which has been shown to range from 1.4 to 3.2, whereas that for daily consumption has been shown to range from 1.8 to 7.5.However, NPC risk is also elevated in association with other preserved food items, including meats, eggs, fruits, and vegetables. (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) In southern China, intake of salted and other preserved foods is particularly high among boat-dwelling fishermen and their families, known as Tankas-the population subgroup at highest risk of developing NPC. Salt-preserved foods are a dietary staple in all NPC-endemic populations. (14,16) Furthermore, salted fish is a traditional weaning food, resulting in early and frequent feeding of infants-especially in the Cantonese population (4,14) and in families of lower socioeconomic status. (3,17) Childhood exposure, especially at weaning seems more strongly related to NPC risk than adulthood exposure. (3,4,(14)(15)(16)(18)(19)(20) This dietary pattern may explain part of the international distribution of NPC incidence.The carcinogenic potential of salt-preserved fish is supported by experiments in rats, which develop malignant nasal and NPC.(21-23) The process of salt preservation is inefficient, allowing fish and other foods to become partially putrefied. (24,25) As a result, these foods accumulate significant levels of nitrosamines, which are known as carcinogens.(24,26-28) Consumption of salted fish is an important source of nitrosamines. NNitrosodimethylamine is the predominant volatile nitrosamine in salted fish. After enzymatic metabolic or bacteria activation, N-nitrosodimethylamine forms an important carcinogenic N-nitroso compounds. (25) In some experiments in rats, the carcinogenecity of nitrosamines and N-nitroso compounds has been proved, for instance diethylnitrosamine (DNE), dimethlbenzanthracene-anthracene (DMBA), and DNP. (6,15,29) In our previous s...

Chemical Carcinogenesis and Nasopharyngeal Carcinoma

“…After establishing the optimal carcinogens and method of administration, we succeeded in the induction of experimental NPC in rats using DNP [57]. This suggests that chemical carcinogens might be among etiologic factors of NPC.…”

“…Table 1. NPC induced in rats by DEN and DMBA The induced tumors resembled human nasopharyngeal cancers but were of a welldifferentiated type, including squamous cell carcinoma (Grade I and II), occasional multiform cell type, and papillary or basal cell carcinomas [57,72,73]. The serial sections of nasopharynx enabled us to trace number, sites, and distribution, as well as histogenesis of experimental NPC.…”

“…The neoplasms were usually moderately or even poorly differentiated squamous carcinomas. This downward growth of neoplasms, which often occurs in human NPC, may cause difficulty in early detection or in producing a good smear of exfoliative cells for cytological diagnosis [57,72,73].…”

“…This growth pattern occurred more frequently in the DNP group, and sometimes formed papillary carcinomas [57,72,73]. The infiltrative carcinomas were usually of a squamous cell type, although basal cell carcinoma was observed occasionally.…”

“…Some of the irregular cords or trabeculae of tumor cells, arising from different portions of the epithelium, might finally fuse together to form a large solid mass of tumor [57,72,73]. It was evident that most of the lesions were multicentric rather than unicentric in origin.…”